Antibodies that immunospecifically bind BLyS

ABSTRACT

The present invention relates to antibodies and related molecules that immunospecifically bind to BLyS. The present invention also relates to methods and compositions for detecting or diagnosing a disease or disorder associated with aberrant BLyS expression or inappropriate function of BLyS comprising antibodies or fragments or variants thereof or related molecules that immunospecifically bind to BLyS. The present invention further relates to methods and compositions for preventing, treating or ameliorating a disease or disorder associated with aberrant BLyS expression or inappropriate BLyS function comprising administering to an animal an effective amount of one or more antibodies or fragments or variants thereof or related molecules that immunospecifically bind to BLyS.

[0001] The present invention relates to antibodies and related moleculesthat immunospecifically bind to BLyS. The present invention also relatesto methods and compositions for detecting, diagnosing, or prognosing adisease or disorder associated with aberrant BLyS or BLyS receptorexpression or inappropriate function of BLyS or BLyS receptor,comprising antibodies or fragments or variants thereof, or relatedmolecules, that immunospecifically bind to BLyS. The present inventionfurther relates to methods and compositions for preventing, treating orameliorating a disease or disorder associated with aberrant BLyS or BLySreceptor expression or inappropriate BLyS function or BLyS receptorfunction, comprising administering to an animal, preferably a human, aneffective amount of one or more antibodies or fragments or variantsthereof, or related molecules, that immunospecifically bind to BLyS.

BACKGROUND OF THE INVENTION

[0002] B lymphocyte stimulator (BLyS) is a member of the tumor necrosisfactor (“TNF”) superfamily that induces both in vivo and in vitro B cellproliferation and differentiation (Moore et al, Science 285: 260-263(1999)). BLyS is distinguishable from other B cell growth anddifferentiation factors such as IL-2, IL-4, IL-5, IL-6, IL-7, IL-13,IL-15, CD40L, or CD27L (CD70) by its monocyte-specific gene and proteinexpression pattern and its specific receptor distribution and biologicalactivity on B lymphocytes. BLyS expression is not detected on naturalkiller (“NK”) cells, T cells or B cells, but is restricted to cells ofmyeloid origin. BLyS expression on resting monocytes is upregulated byinterferon-gamma (IFN-gamma). The gene encoding BLyS has been mapped tochromosome 13q34.

[0003] BLyS is expressed as a 285 amino acid type II membrane-boundpolypeptide and a soluble 152 amino acid polypeptide (Moore et al., 1999supra). The membrane-bound form of BLyS has a predicted transmembranespanning domain between amino acid residues 47 and 73. The NH₂-terminusof the soluble form of BLyS begins at Ala¹³⁴ of the membrane-bound formof BLyS. Soluble recombinant BLyS has been shown to induce in vitroproliferation of murine splenic B cells and to bind to a cell-surfacereceptor on these cells (Moore et al., 1999 supra). Soluble BLySadministration to mice has been shown to result in an increase in theproportion of CD45R^(dull), Ly6D^(bright) (also known as ThB) B cellsand an increase in serum IgM and IgA levels (Moore et al., 1999 supra).Thus, BLyS displays a B cell tropism in both its receptor distributionand biological activity.

[0004] Based upon its expression pattern and biological activity, BLyShas been suggested to be involved in the exchange of signals between Bcells and monocytes or their differentiated progeny. The restrictedexpression patterns of BLyS receptor and ligand suggest that BLyS mayfunction as a regulator of T cell-independent responses in a manneranalogous to that of CD40 and CD40L in T cell-dependent antigenactivation. As such, antibodies and related molecules thatimmunospecifically bind to BLyS may find medical utility in, forexample, the treatment of B cell disorders associated with autoimmunity,neoplasia, or immunodeficiency syndromes.

SUMMARY OF THE INVENTION

[0005] The present invention encompasses antibodies (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) that immunospecifically bind to a polypeptide orpolypeptide fragment of BLyS. In particular, the invention encompassesantibodies (including molecules comprising, or alternatively consistingof, antibody fragments or variants thereof) that immunospecifically bindto a polypeptide or polypeptide fragment of human BLyS (SEQ ID NOS:3228and/or 3229) or BLyS expressed on human monocytes; murine BLyS (SEQ IDNOS:3230 and/or 3231) or BLyS expressed on murine monocytes; rat BLyS(either the soluble forms as given in SEQ ID NOS:3232, 3233, 3234 and/or3235 or in a membrane associated form, e.g., on the surface of ratmonocytes); or monkey BLyS (e.g., the monkey BLyS polypeptides of SEQ IDNOS:3236 and/or 3237, the soluble form of monkey BLyS, or BLyS expressedon monkey monocytes), preferably human BLyS. The present invention alsoencompasses methods and compositions for detecting, diagnosing, orprognosing diseases or disorders associated with aberrant BLyS or BLySreceptor expression or inappropriate function of BLyS or BLyS receptorin an animal, preferably a mammal, and most preferably a human,comprising, or alternatively consisting of, use of antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to BLyS. Diseases anddisorders which can be detected, diagnosed, or prognosed with theantibodies (including molecules comprising, or alternatively consistingof, antibody fragments or variants thereof) of the invention include,but are not limited to, immune disorders (e.g., lupus, rheumatoidarthritis, multiple sclerosis, myasthenia gravis, Hashimoto's disease,and immunodeficiency syndrome), inflammatory disorders (e.g., asthma,allergic disorders, and rheumatoid arthritis), infectious diseases(e.g., AIDS), and proliferative disorders (e.g., leukemia, carcinoma,and lymphoma). The present invention further encompasses methods andcompositions for preventing, treating or ameliorating diseases ordisorders associated with aberrant BLyS or BLyS receptor expression orinappropriate function of BLyS or BLyS receptor in an animal, preferablya mammal, and most preferably a human, comprising, or alternativelyconsisting of, administering to said animal an effective amount of oneor more antibodies (including molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof) thatimmunospecifically bind to BLyS. Diseases and disorders which can beprevented, treated or ameliorated by administering an effective amountof an antibody of the invention include, but are not limited to, immunedisorders (e.g., lupus, rheumatoid arthritis, multiple sclerosis,myasthenia gravis, Hashimoto's disease, and immunodeficiency syndrome),inflammatory disorders (e.g., asthma, allergic disorders, and rheumatoidarthritis), infectious diseases (e.g., AIDS), and proliferativedisorders (e.g., leukemia, carcinoma, and lymphoma).

[0006] Using phage display technology, the present inventors haveidentified single chain antibody molecules (“scFvs”) thatimmunospecifically bind to BLyS, including scFvs that immunospecificallybind to soluble BLyS, scFvs that immunospecifically bind themembrane-bound form of BLyS, and scFvs that immunospecifically bind toboth the soluble form and the membrane-bound form of BLyS. Moleculescomprising, or alternatively consisting of, fragments or variants ofthese scFvs (e.g., including VH domains, VH CDRs, VL domains, or VL CDRshaving an amino acid sequence of any one of those referred to in Table1), that immunospecifically bind the soluble form of BLyS, themembrane-bound form of BLyS, and/or both the soluble form andmembrane-bound form of BLyS, are also encompassed by the invention, asare nucleic acid molecules that encode these scFvs, and/or molecules.

[0007] In particular, the invention relates to scFvs comprising, oralternatively consisting of, an amino acid sequence selected from thegroup consisting of SEQ ID NOS: 1-2128, preferably SEQ ID NOS:834-872,1570-1595, and 1886-1908, and most preferably SEQ ID NOS:1-46, 321-329,1563-1569, and 1881-1885, as referred to in Table 1 below. In specificembodiments, the present invention relates to scFvs thatimmunospecifically bind the soluble form of BLyS, said scFvs comprising,or alternatively consisting of, an amino acid sequence of SEQ ID NOS:1563-1569, preferably SEQ ID NOS:1570-1595, and most preferably SEQ IDNOS: 1563-1569, as referred to in Table 1, below. In other embodiments,the present invention also relates to scFvs that immunospecifically bindthe membrane-bound form of BLyS, said scFvs comprising, or alternativelyconsisting of, an amino acid sequence of SEQ ID NOS: 1881-2128,preferably SEQ ID NOS:1886-1908, and most preferably SEQ ID NOS:1881-1885, as referred to in Table 1 below. The present inventionfurther relates to scFvs that immunospecifically bind both themembrane-bound form and soluble form of BLyS, said scFvs comprising, oralternatively consisting of, an amino acid sequence of SEQ ID NOS:1-1562, preferably SEQ ID NOS: 834-872, and most preferably SEQ ID NOS:1-46, and 321-329, as referred to in Table 1 below. Moleculescomprising, or alternatively consisting of, fragments or variants ofthese scFvs (e.g., including VH domains, VH CDRs, VL domains, or VL CDRshaving an amino acid sequence of any one of those referred to in Table1), that immunospecifically bind the soluble form of BLyS, themembrane-bound form of BLyS, and/or both the soluble form andmembrane-bound form of BLyS, are also encompassed by the invention, asare nucleic acid molecules that encode these scFvs, and/or molecules.

[0008] The present invention provides antibodies (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) that immunospecifically bind to a polypeptide orpolypeptide fragment of BLyS, said antibodies comprising, oralternatively consisting of, a polypeptide having the amino acidsequence of any one of the variable heavy (“VH”) domains referred to inTable 1, below, or any one of the variable light (“VL”) domains referredto in Table 1. In a preferred embodiment, antibodies of the presentinvention comprise, or alternatively consist of, a polypeptide havingthe amino acid sequence of a VH domain contained in SEQ ID NOS: 1-46,321-329, 834-872, 1563-1595, or 1881-1908, as referred to in Table 1below. In another preferred embodiment, antibodies (including moleculescomprising or alternatively consisting of, antibody fragments orvariants thereof) of the present invention comprise, or alternativelyconsist of, a polypeptide having the amino acid sequence of a VL domaincontained SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908, asreferred to in Table 1 below. Molecules comprising, or alternativelyconsisting of, fragments or variants of these antibodies (e.g.,including VH domains, VH CDRs, VL domains, or VL CDRs having an aminoacid sequence of any one of those referred to in Table 1), thatimmunospecifically bind the soluble form of BLyS, the membrane-boundform of BLyS, and/or both the soluble form and membrane-bound form ofBLyS, are also encompassed by the invention, as are nucleic acidmolecules that encode these antibodies, and/or molecules.

[0009] The present invention also provides antibodies (includingmolecules comprising or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to a polypeptide or apolypeptide fragment of BLyS, said antibodies comprising, oralternatively consisting of, a polypeptide having the amino acidsequence of any one of the VH domains referred to in Table 1, below, andany one of the VL domains referred to in Table 1. In a preferredembodiment, the antibodies of the invention comprise or alternativelyconsist of, a polypeptide having the amino acid sequence of a VH and VLdomain contained in the same scFv referred to in Table 1. In anotherpreferred embodiment, antibodies of the present invention, comprise, oralternatively consist of, a VH domain from an scFv of SEQ ID NOS:1-46,321-329, 834-872, 1563-1595, or 1881-1908, as disclosed in Table 1, anda VL domain from an scFv SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595,or 1881-1908, as disclosed in Table 1. In another preferred embodiment,antibodies of the present invention comprise, or alternatively consistof, the VH and VL domain from a single scFv of SEQ ID NOS:1-46, 321-329,834-872, 1563-1595, or 1881-1908, as disclosed in Table 1. Moleculescomprising, or alternatively consisting of, fragments or variants ofthese antibodies (e.g., including VH domains, VH CDRs, VL domains, or VLCDRs having an amino acid sequence of any one of those referred to inTable 1), that immunospecifically bind the soluble form of BLyS, themembrane-bound form of BLyS, and/or both the soluble form andmembrane-bound form of BLyS, are also encompassed by the invention, asare nucleic acid molecules that encode these antibodies, and/ormolecules.

[0010] The present invention also provides antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to a polypeptide or apolypeptide fragment of BLyS, said antibodies comprising, oralternatively consisting of, a polypeptide having the amino acidsequence of any one, two, three or more of the VH complementaritydetermining regions (“CDRs”) (i.e., VH CDR1, VH CDR2, or VH CDR3)referred to in Table 1 and/or any one, two, three or more of the VL CDRs(i.e., VL CDR1, VL CDR2, or VL CDR3) referred to in Table 1. In oneembodiment, antibodies of the present invention comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof any one of the VH CDR1s referred to in Table 1 and/or any one of theVL CDR1s referred to in Table 1. In another embodiment, antibodies ofthe present invention comprise, or alternatively consist of, apolypeptide having the amino acid sequence of any one of the VH CDR2sreferred to in Table 1 and/or any one of the VL CDR2s referred to inTable 1. In a preferred embodiment, antibodies of the present inventioncomprise, or alternatively consist of, a polypeptide having the aminoacid sequence of any one of the VH CDR3s referred to in Table 1 and/orany one of the VL CDR3s referred to in Table 1. Molecules comprising, oralternatively consisting of, fragments or variants of these antibodies(e.g., including VH domains, VH CDRs, VL domains, or VL CDRs having anamino acid sequence of any one of those referred to in Table 1), thatimmunospecifically bind the soluble form of BLyS, the membrane-boundform of BLyS, and/or both the soluble form and membrane-bound form ofBLyS, are also encompassed by the invention, as are nucleic acidmolecules that encode these antibodies, and/or molecules.

[0011] In another embodiment, antibodies of the present invention(including molecules comprising, or alternatively consisting of,antibody fragments or variants thereof) immunospecifically bind to apolypeptide or polypeptide fragment of BLyS, and comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof any one of the VH CDR1s referred to in Table 1, any one of the VHCDR2s referred to in Table 1, and/or any one of the VH CDR3s referred toin Table 1. In another embodiment, antibodies of the present inventioncomprise, or alternatively consist of, a polypeptide having the aminoacid sequence of any one of the VL CDR1s referred to in Table 1, any oneof the VL CDR2s referred to in Table 1, and/or any one of the VL CDR3sreferred to in Table 1. In a preferred embodiment, antibodies of thepresent invention comprise, or alternatively consist of, at least one,two, three, four, five, six, or more CDRs that correspond to the samescFv referred to in Table 1, more preferably where CDR1, CDR2, and CDR3of the VL domain correspond to the same scFv or where CDR1, CDR2, andCDR3 of the VH domain correspond to the same scFv, and most preferablywhere all six CDRs correspond to the same scFv referred to in Table 1.Molecules comprising, or alternatively consisting of, fragments orvariants of these antibodies (e.g., including VH domains, VH CDRs, VLdomains, or VL CDRs having an amino acid sequence of any one of thosereferred to in Table 1), that immunospecifically bind the soluble formof BLyS, the membrane-bound form of BLyS, and/or both the soluble formand membrane-bound form of BLyS, are also encompassed by the invention,as are nucleic acid molecules that encode these antibodies, and/ormolecules.

[0012] The present invention also provides antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that: immunospecifically bind to the soluble formof BLyS (e.g., a polypeptide consisting of amino acids 134-285 of SEQ IDNO:3228); that immunospecifically bind to the membrane-bound form ofBLyS (e.g., a polypeptide consisting of amino acids 1-285 of SEQ IDNO:3228 or a BLyS polypeptide expressed on the surface of monocytes)and/or that immunospecifically bind to both the soluble form andmembrane-bound form of BLyS. In a preferred embodiment, antibodies ofthe present invention immunospecifically bind to the soluble form ofBLyS and comprise, or alternatively consist of, a VH domain, VH CDR1, VHCDR2, VH CDR3, VL domain, VL CDR1, VL CDR2, and/or VL CDR3 correspondingto one or more scFvs, that immunospecifically bind to the soluble formof BLyS. In another preferred embodiment, antibodies of the presentinvention immunospecifically bind to the membrane-bound form of BLyS andcomprise, or alternatively consist of, a VH domain, VH CDR1, VH CDR2, VHCDR3, VL domain, VL CDR1, VL CDR2, and/or VL CDR3 corresponding to oneor more scFvs, that immunospecifically bind to the membrane-bound formof BLyS. In yet another preferred embodiment, antibodies of the presentinvention immunospecifically bind to the soluble form and membrane-boundform of BLyS and comprise, or alternatively consist of, a VH domain, VHCDR1, VH CDR2, VH CDR3, VL domain, VL CDR1, VL CDR2, and/or VL CDR3corresponding to one or more scFvs, that immunospecifically binds to thesoluble form and membrane-bound form of BLyS. In another preferredembodiment, antibodies of the present invention comprise, oralternatively consist of, a VH domain and a VL domain corresponding tothe same scFv disclosed in Table 1, which antibodies immunospecificallybind to the soluble form of BLyS, the membrane-bound form of BLyS, orboth the soluble form and membrane-bound form of BLyS. Nucleic acidmolecules encoding these antibodies are also encompassed by theinvention. Molecules comprising, or alternatively consisting of,fragments or variants of these antibodies (e.g., including VH domains,VH CDRs, VL domains, or VL CDRs having an amino acid sequence of any oneof those referred to in Table 1), that immunospecifically bind thesoluble form of BLyS, the membrane-bound form of BLyS, and/or both thesoluble form and membrane-bound form of BLyS, are also encompassed bythe invention, as are nucleic acid molecules that encode theseantibodies, and/or molecules.

[0013] A VH domain of an amino acid sequence disclosed herein may becombined with

[0014] a VL domain of an amino acid sequence disclosed herein, or otherVL domains, to provide a VH/VL pairing representing an antigen-bindingsite of an antibody. Similarly, a VL domain of an amino acid sequencedisclosed herein may be combined with a VH domain of an amino acidsequence disclosed herein, or other VH domains. Further, one or moreCDRs disclosed herein may be taken from a VH or VL domain andincorporated into a suitable framework as discussed infra.

[0015] The present invention provides antibodies (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof (including derivatives)) comprising, or alternativelyconsisting of, of VH domains, VL domains and/or CDRs described herein,which antibodies, immunospecifically bind to BLyS (e.g., soluble BLySand membrane-bound BLyS) and can be routinely assayed for immunospecificbinding to BLyS using methods known in the art, such as, for example,the immunoassays disclosed infra. Antibodies and antibody fragments orvariants (including derivatives) of the invention may include, forexample, one or more amino acid sequence alterations (addition,deletion, substitution and/or insertion of an amino acid residue). Thesealterations may be made in one or more framework regions and/or one ormore CDR's. The antibodies of the invention (including antibodyfragments, and variants and derivative thereof) can be routinely made bymethods known in the art. Molecules comprising, or alternativelyconsisting of, fragments or variants of any of the VH domains, VH CDRs,VL domains, and VL CDRs whose sequences are specifically disclosedherein may be employed in accordance with the present invention. Nucleicacid molecules encoding these antibodies and molecules (includingfragments, variants, and derivatives) are also encompassed by theinvention.

[0016] The present invention also provides panels of antibodies(including molecules comprising, or alternatively consisting of,antibody fragments or variants) wherein the panel members correspond toone, two, three, four, five, ten, fifteen, twenty, or more differentantibodies of the invention (e.g., whole antibodies, Fabs, F(ab′)₂fragments, Fd fragments, disulfide-linked Fvs (sdFvs), antiidiotypic(anti-Id) antibodies, and scFvs). The present invention further providesmixtures of antibodies, wherein the mixture corresponds to one, two,three, four, five, ten, fifteen, twenty, or more different antibodies ofthe invention (e.g., whole antibodies, Fabs, F(ab′)₂ fragments, Fdfragments, disulfide-linked Fvs (sdFvs), antiidiotypic (anti-Id)antibodies, and scFvs)). The present invention also provides forcompositions comprising, or alternatively consisting of, one, two,three, four, five, ten, fifteen, twenty, or more antibodies of thepresent invention (including molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof). A composition ofthe invention may comprise, or alternatively consist of, one, two,three, four, five, ten, fifteen, twenty, or more amino acid sequences ofone or more antibodies or fragments or variants thereof. Alternatively,a composition of the invention may comprise, or alternatively consistof, nucleic acid molecules encoding one or more antibodies of theinvention.

[0017] The present invention also provides for fusion proteinscomprising an antibody (including molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof) of the invention,and a heterologous polypeptide (i.e., a polypeptide unrelated to anantibody or antibody domain). Nucleic acid molecules encoding thesefusion proteins are also encompassed by the invention. A composition ofthe present invention may comprise, or alternatively consist of, one,two, three, four, five, ten, fifteen, twenty or more fusion proteins ofthe invention. Alternatively, a composition of the invention maycomprise, or alternatively consist of, nucleic acid molecules encodingone, two, three, four, five, ten, fifteen, twenty or more fusionproteins of the invention.

[0018] The present invention also provides for a nucleic acid molecule,generally

[0019] isolated, encoding an antibody (including molecules such asscFvs, which comprise, or alternatively consist of, an antibody fragmentor variant thereof) of the invention. The present invention alsoprovides a host cell transformed with a nucleic acid molecule of theinvention and progeny thereof. The present invention also provides amethod for the production of an antibody (including a moleculecomprising, or alternatively consisting of, an antibody fragment orvariant thereof) of the invention. The present invention furtherprovides a method of expressing an antibody (including a moleculecomprising, or alternatively consisting of, an antibody fragment orvariant thereof) of the invention from a nucleic acid molecule. Theseand other aspects of the invention are described in further detailbelow.

[0020] The present invention also encompasses methods and compositionsfor detecting, diagnosing and/or prognosing diseases or disordersassociated with aberrant BLyS or BLyS receptor expression orinappropriate BLyS or BLyS receptor function in an animal, preferably amammal, and most preferably a human, comprising using antibodies(including molecules which comprise, or alternatively consist of,antibody fragments or variants thereof) that immunospecifically bind toBLyS. Diseases and disorders which can be detected, diagnosed orprognosed with the antibodies of the invention include, but are notlimited to, immune disorders (e.g., lupus, rheumatoid arthritis,multiple sclerosis, myasthenia gravis, Hashimoto's disease, andimmunodeficiency syndrome), inflammatory disorders (e.g., asthma,allergic disorders, and rheumatoid arthritis), infectious diseases(e.g., AIDS), and proliferative disorders (e.g., leukemia, carcinoma,and lymphoma).

[0021] In specific embodiments, the present invention encompassesmethods and compositions for detecting, diagnosing and/or prognosingdiseases or disorders associated with hypergammaglobulinemia (e.g.,AIDS, autoimmune diseases, and some immunodeficiencies). In otherspecific embodiments, the present invention encompasses methods andcompositions for detecting, diagnosing and/or prognosing diseases ordisorders associated with hypogammaglobulinemia (e.g., animmunodeficiency).

[0022] The present invention further encompasses methods andcompositions for preventing, treating or ameliorating diseases ordisorders associated with aberrant BLyS or BLyS receptor expression orinappropriate BLyS or BLyS receptor function in an animal, preferably amammal, and most preferably a human, comprising administering to saidanimal an effective amount of one or more antibodies (includingmolecules which comprise, or alternatively consist of, antibodyfragments or variants thereof) that immunospecifically bind to BLyS.Diseases and disorders which can be prevented, treated or inhibited byadministering an effective amount of one or more antibodies or moleculesof the invention include, but are not limited to, immune disorders(e.g., lupus, rheumatoid arthritis, multiple sclerosis, myastheniagravis, Hashimoto's disease, and immunodeficiency syndrome),inflammatory disorders (e.g., asthma, allergic disorders, and rheumatoidarthritis), infectious diseases (e.g., AIDS), and proliferativedisorders (e.g., leukemia, carcinoma, and lymphoma).

[0023] In specific embodiments, the present invention encompassesmethods and compositions (e.g., antagonistic anti-BLyS antibodies) forpreventing, treating or ameliorating diseases or disorders associatedwith hypergammaglobulinemia (e.g., AIDS, autoimmune diseases, and someimmunodeficiency syndromes). In other specific embodiments, the presentinvention encompasses methods and compositions (e.g., agonisticanti-BLyS antibodies) for preventing, treating or ameliorating diseasesor disorders associated with hypogammaglobulinemia (e.g., animmunodeficiency syndrome).

[0024] Autoimmune disorders, diseases, or conditions that may bedetected, diagnosed, prognosed, or monitored using the antibodies of theinvention include, but are not limited to, autoimmune hemolytic anemia,autoimmune neonatal thrombocytopenia, idiopathic thrombocytopeniapurpura, autoimmune neutropenia, autoimmunocytopenia, hemolytic anemia,antiphospholipid syndrome, dermatitis, gluten-sensitive enteropathy,allergic encephalomyelitis, myocarditis, relapsing polychondritis,rheumatic heart disease, glomerulonephritis (e.g., IgA nephropathy),Multiple Sclerosis, Neuritis, Uveitis Ophthalmia, Polyendocrinopathies,Purpura (e.g., Henloch-Scoenlein purpura), Reiter's Disease, Stiff-ManSyndrome, Autoimmune Pulmonary Inflammation, myocarditis, IgAglomerulonephritis, dense deposit disease, rheumatic heart disease,Guillain-Barre Syndrome, insulin dependent diabetes mellitis, andautoimmune inflammatory eye, autoimmune thyroiditis, hypothyroidism(i.e., Hashimoto's thyroiditis, systemic lupus erhythematosus, discoidlupus, Goodpasture's syndrome, Pemphigus, Receptor autoimmunities suchas, for example, (a) Graves' Disease, (b) Myasthenia Gravis, and (c)insulin resistance, autoimmune hemolytic anemia, autoimmunethrombocytopenic purpura, rheumatoid arthritis, schleroderma withanti-collagen antibodies, mixed connective tissue disease,polymyositis/dermatomyositis, pernicious anemia, idiopathic Addison'sdisease, infertility, glomerulonephritis such as primaryglomerulonephritis and IgA nephropathy, bullous pemphigoid, Sjögren'ssyndrome, diabetes mellitus, and adrenergic drug resistance (includingadrenergic drug resistance with asthma or cystic fibrosis), chronicactive hepatitis, primary biliary cirrhosis, other endocrine glandfailure, vitiligo, vasculitis, post-MI, cardiotomy syndrome, urticaria,atopic dermatitis, asthma, inflammatory myopathies, and otherinflammatory, granulomatous, degenerative, and atrophic disorders).

[0025] Immunodeficiencies that may be detected, diagnosed, prognosed, ormonitored using the antibodies of the invention include, but are notlimited to, severe combined immunodeficiency (SCID)-X linked,SCID-autosomal, adenosine deaminase deficiency (ADA deficiency),X-linked agammaglobulinemia (XLA), Bruton's disease, congenitalagammaglobulinemia, X-linked infantile agammaglobulinemia, acquiredagammaglobulinemia, adult onset agammaglobulinemia, late-onsetagammaglobulinemia, dysgammaglobulinemia, hypogammaglobulinemia,transient hypogammaglobulinemia of infancy, unspecifiedhypogammaglobulinemia, agammaglobulinemia, common variableimmunodeficiency (CVID) (acquired), Wiskott-Aldrich Syndrome (WAS),X-linked immunodeficiency with hyper IgM, non X-linked immunodeficiencywith hyper IgM, selective IgA deficiency, IgG subclass deficiency (withor without IgA deficiency), antibody deficiency with normal or elevatedIgs, immunodeficiency with thymoma, Ig heavy chain deletions, kappachain deficiency, B cell lymphoproliferative disorder (BLPD), selectiveIgM immunodeficiency, recessive agammaglobulinemia (Swiss type),reticular dysgenesis, neonatal neutropenia, severe congenitalleukopenia, thymic alymphoplasia-aplasia or dysplasia withimmunodeficiency, ataxia-telangiectasia, short limbed dwarfism, X-linkedlymphoproliferative syndrome (XLP), Nezelof syndrome-combinedimmunodeficiency with Igs, purine nucleoside phosphorylase deficiency(PNP), MHC Class II deficiency (Bare Lymphocyte Syndrome) and severecombined immunodeficiency.

[0026] Definitions

[0027] The term “antibody,” as used herein, refers to immunoglobulinmolecules and immunologically active portions of immunoglobulinmolecules, i.e., molecules that contain an antigen binding site thatimmunospecifically binds an antigen. As such, the term antibodyencompasses not only whole antibody molecules, but also antibodyfragments as well as variants (including derivatives) of antibodies andantibody fragments. Examples of molecules which are described by theterm “antibody” in this application include, but are not limited to:single chain Fvs (scFvs), Fab fragments, Fab′ fragments, F(ab′)₂,disulfide linked Fvs (sdFvs), Fvs, and fragments comprising oralternatively consisting of, either a VL or a VH domain. The term“single chain Fv” or “scFv” as used herein refers to a polypeptidecomprising a VL domain of antibody linked to a VH domain of an antibody.Antibodies that immunospecifically bind to BLyS may havecross-reactivity with other antigens. Preferably, antibodies thatimmunospecifically bind to BLyS do not cross-react with other antigens.Antibodies that immunospecifically bind to BLyS can be identified, forexample, by immunoassays or other techniques known to those of skill inthe art, e.g., the immunoassays described in the Examples below.

[0028] Antibodies of the invention include, but are not limited to,monoclonal, multispecific, human or chimeric antibodies, single chainantibodies, Fab fragments, F(ab′) fragments, antiidiotypic (anti-Id)antibodies (including, e.g., anti-Id antibodies to antibodies of theinvention), and epitope-binding fragments of any of the above. Theimmunoglobulin molecules of the invention can be of any type (e.g., IgG,IgE, IgM, IgD, IgA and IgY), class (e.g., IgG₁, IgG₂, IgG₃, IgG₄, IgA₁,and IgA2) or subclass of immunoglobulin molecule.

[0029] Preferably, an antibody of the invention comprises, oralternatively consists of, a VH domain, VH CDR, VL domain, or VL CDRhaving an amino acid sequence of any one of those referred to in Table1, or a fragment or variant thereof.

[0030] An antibody of the invention “which binds the soluble form ofBLyS” is one which binds the 152 amino acid soluble form of the BLySprotein (amino acids 134-285 of SEQ ID NO:3228). In specific embodimentsof the invention, an antibody of the invention “which binds the solubleform of BLyS” does not also bind the membrane-bound ormembrane-associated form of BLyS. Assays which measure binding to thesoluble form of BLyS include, but are not limited to, receptor bindinginhibition assay or capture of soluble BLyS from solution as describedin Examples 8 and 9.

[0031] An antibody of the invention “which binds the membrane-bound formof BLyS” is one which binds the membrane-associated (uncleaved) BLySprotein. In specific embodiments of the invention, an antibody of theinvention “which binds the membrane-bound form of BLyS” does not alsobind the soluble form of BLyS. Binding to HIS-tagged BLyS (as describedherein) in an ELISA is an indicator that an antibody binds themembrane-bound form of BLyS, but should not be relied upon as proof ofspecificity for the membrane-bound form of BLyS. Assays that may berelied upon as proof of an antibody's specificity for membrane-boundBLyS, include, but are not limited to, binding to plasma membranesexpressing BLyS as described in Example 2. An antibody of the invention“which binds the both the soluble form and the membrane-bound form ofBLyS” is one which binds both the membrane-bound form and the solubleform of BLyS.

[0032] The term “variant” as used herein refers to a polypeptide thatpossesses a similar or identical function as a BLyS polypeptide, afragment of BLyS, an anti-BLyS antibody or antibody fragment thereof,but does not necessarily comprise a similar or identical amino acidsequence of a BLyS polypeptide, a fragment of BLyS, an anti-BLySantibody or antibody fragment thereof, or possess a similar or identicalstructure of a BLyS polypeptide, a fragment of BLyS, an anti-BLySantibody or antibody fragment thereof. A variant having a similar aminoacid refers to a polypeptide that satisfies at least one of thefollowing: (a) a polypeptide comprising, or alternatively consisting of,an amino acid sequence that is at least 30%, at least 35%, at least 40%,at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95% or at least 99% identical to the amino acid sequence of a BLySpolypeptide, a fragment of BLyS, an anti-BLyS antibody or antibodyfragment thereof (including a VH domain, VHCDR, VL domain, or VLCDRhaving an amino acid sequence of any one of those referred to inTable 1) described herein; (b) a polypeptide encoded by a nucleotidesequence, the complementary sequence of which hybridizes under stringentconditions to a nucleotide sequence encoding a BLyS polypeptide (e.g.,SEQ ID NO:3228), a fragment of BLyS, an anti-BLyS antibody or antibodyfragment thereof (including a VH domain, VHCDR, VL domain, or VLCDRhaving an amino acid sequence of any one of those referred to in Table1), described herein, of at least 5 amino acid residues, at least 10amino acid residues, at least 15 amino acid residues, at least 20 aminoacid residues, at least 25 amino acid residues, at least 30 amino acidresidues, at least 40 amino acid residues, at least 50 amino acidresidues, at least 60 amino residues, at least 70 amino acid residues,at least 80 amino acid residues, at least 90 amino acid residues, atleast 100 amino acid residues, at least 125 amino acid residues, or atleast 150 amino acid residues; and (c) a polypeptide encoded by anucleotide sequence that is at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95% or at least 99%, identical to the nucleotide sequence encodinga BLyS polypeptide, a fragment of BLyS, an anti-BLyS antibody orantibody fragment thereof (including a VH domain, VHCDR, VL domain, orVLCDR having an amino acid sequence of any one of those referred to inTable 1), described herein. A polypeptide with similar structure to aBLyS polypeptide, a fragment of BLyS, an anti-BLyS antibody or antibodyfragment thereof, described herein refers to a polypeptide that has asimilar secondary, tertiary or quartemary structure of a BLySpolypeptide, a fragment of BLyS, an anti-BLyS antibody, or antibodyfragment thereof, described herein. The structure of a polypeptide candetermined by methods known to those skilled in the art, including butnot limited to, X-ray crystallography, nuclear magnetic resonance, andcrystallographic electron microscopy.

[0033] To determine the percent identity of two amino acid sequences orof two nucleic acid sequences, the sequences are aligned for optimalcomparison purposes (e.g., gaps can be introduced in the sequence of afirst amino acid or nucleic acid sequence for optimal alignment with asecond amino acid or nucleic acid sequence). The amino acid residues ornucleotides at corresponding amino acid positions or nucleotidepositions are then compared. When a position in the first sequence isoccupied by the same amino acid residue or nucleotide at thecorresponding position in the second sequence, then the molecules areidentical at that position. The percent identity between the twosequences is a function of the number of identical positions shared bythe sequences (i.e., % identity=number of identical overlappingpositions/total number of positions×100%). In one embodiment, the twosequences are the same length.

[0034] The determination of percent identity between two sequences canbe accomplished using a mathematical algorithm known to those of skillin the art. An example of a mathematical algorithm for comparing twosequences is the algorithm of Karlin and Altschul Proc. Natl. Acad. Sci.USA 87:2264-2268(1990), modified as in Karlin and Altschul Proc. Natl.Acad. Sci. USA 90:5873-5877(1993). The BLASTn and BLASTx programs ofAltschul, et al. J. Mol. Biol. 215:403-410(1990) have incorporated suchan alogrithm. BLAST nucleotide searches can be performed with the BLASTnprogram, score=100, wordlength=12 to obtain nucleotide sequenceshomologous to a nucleic acid molecules of the invention. BLAST proteinsearches can be performed with the BLASTx program, score=50,wordlength=3 to obtain amino acid sequences homologous to a proteinmolecules of the invention. To obtain gapped alignments for comparisonpurposes, Gapped BLAST can be utilized as described in Altschul et al.Nucleic Acids Res. 25:3389-3402(1997). Alternatively, PSI-BLAST can beused to perform an iterated search which detects distant relationshipsbetween molecules (Id.). When utilizing BLAST, Gapped BLAST, andPSI-BLAST programs, the default parameters of the respective programs(e.g., BLASTx and BLASTn) can be used. (Seehttp://www.ncbi.nlm.nih.gov.)

[0035] Another example of a mathematical algorithm utilized for thecomparison of sequences is the algorithm of Myers and Miller, CABIOS(1989). The ALIGN program (version 2.0) which is part of the GCGsequence alignment software package has incorporated such an alogrithm.Other algorithms for sequence analysis known in the art include ADVANCEand ADAM as described in Torellis and Robotti Comput. Appl. Biosci.,10:3-5(1994); and FASTA described in Pearson and Lipman Proc. Natl.Acad. Sci. 85:2444-8(1988). Within FASTA, ktup is a control option thatsets the sensitivity and speed of the search.

[0036] The term “derivative” as used herein, refers to a variantpolypeptide of the invention that comprises, or alternatively consistsof, an amino acid sequence of a BLyS polypeptide, a fragment of BLyS, oran antibody of the invention that immunospecifically binds to BLyS,which has been altered by the introduction of amino acid residuesubstitutions, deletions or additions. The term “derivative” as usedherein also refers to a BLyS polypeptide, a fragment of BLyS, anantibody that immunospecifically binds to BLyS which has been modified,e.g., by the covalent attachment of any type of molecule to thepolypeptide. For example, but not by way of limitation, a BLySpolypeptide, a fragment of BLyS, or an anti-BLyS antibody, may bemodified, e.g., by glycosylation, acetylation, pegylation,phosphorylation, amidation, derivatization by known protecting/blockinggroups, proteolytic cleavage, linkage to a cellular ligand or otherprotein, etc. A derivative of a BLyS polypeptide, a fragment of BLyS, oran anti-BLyS antibody, may be modified by chemical modifications usingtechniques known to those of skill in the art, including, but notlimited to, specific chemical cleavage, acetylation, formylation,metabolic synthesis of tunicamycin, etc. Further, a derivative of a BLySpolypeptide, a fragment of BLyS, or an anti-BLyS antibody, may containone or more non-classical amino acids. A polypeptide derivativepossesses a similar or identical function as a BLyS polypeptide, afragment of BLyS, or an anti-BLyS antibody, described herein.

[0037] The term “epitopes” as used herein refers to portions of BLyShaving antigenic or immunogenic activity in an animal, preferably amammal. An epitope having immunogenic activity is a portion of BLyS thatelicits an antibody response in an animal. An eptiope having antigenicactivity is a portion of BLyS to which an antibody immunospecificallybinds as determined by any method known in the art, for example, by theimmunoassays described herein. Antigenic epitopes need not necessarilybe immunogenic.

[0038] The term “fragment” as used herein refers to a polypeptidecomprising an amino acid sequence of at least 5 amino acid residues, atleast 10 amino acid residues, at least 15 amino acid residues, at least20 amino acid residues, at least 25 amino acid residues, at least 30amino acid residues, at least 35 amino acid residues, at least 40 aminoacid residues, at least 45 amino acid residues, at least 50 amino acidresidues, at least 60 amino residues, at least 70 amino acid residues,at least 80 amino acid residues, at least 90 amino acid residues, atleast 100 amino acid residues, at least 125 amino acid residues, atleast 150 amino acid residues, at least 175 amino acid residues, atleast 200 amino acid residues, or at least 250 amino acid residues, ofthe amino acid sequence of BLyS, or an anti-BLyS antibody (includingmolecules such as scFv's, that comprise, or alternatively consist of,antibody fragments or variants thereof) that immunospecifically binds toBLyS.

[0039] The term “fusion protein” as used herein refers to a polypeptidethat comprises, or alternatively consists of, an amino acid sequence ofan anti-BLyS antibody of the invention and an amino acid sequence of aheterologous polypeptide (i.e., a polypeptide unrelated to an antibodyor antibody domain).

[0040] The term “host cell” as used herein refers to the particularsubject cell transfected with a nucleic acid molecule and the progeny orpotential progeny of such a cell. Progeny may not be identical to theparent cell transfected with the nucleic acid molecule due to mutationsor environmental influences that may occur in succeeding generations orintegration of the nucleic acid molecule into the host cell genome.

DESCRIPTION OF THE FIGURES

[0041]FIG. 1. ELISA results for three scFvs, I006E07, I008D05 andI016F04, that immunospecifically bind to U937 membranes, but not to bindto or cross-react with TNF-alpha or BSA.

[0042]FIG. 2. The results for three scFvs, I016H07, I001C09 and I018D07,in a receptor inhibition assay.

[0043]FIG. 3. ELISA results for two scFvs (I022D01 and I031F02)demonstrating their ability to bind to human BLyS and to cross-reactwith mouse BLyS, but not to bind to or cross-react with other antigensof the TNF ligand family.

[0044]FIG. 4. ELISA results for three scFvs (I031F09, I050A12, andI051C04) binding to U937 plasma membranes when either BLyS or TNF-alphais used as a competitor.

[0045]FIG. 5. Kinetic analysis of scFv antibody I003C02. A dilutionseries of I003C02 from 3 nM to 825 nM is shown. Association anddissociation curves were generated using a BIAcore 2000 andBIAevaluation 3.0 software.

[0046]FIG. 6. Typical titration curves for two scFv antibodies (I007F11and I050A07) are shown in FIG. 6. Unlabelled BLyS competed for bindingto its receptor with an IC₅₀ value of 0.8 nM. The IC₅₀ values forI007F11 and I050A07 are 7.9 nM and 17.1 nM, respectively. The assay wasperformed in triplicate and standard error bars are shown.

[0047]FIG. 7. ELISA results for three scFvs clones (I074B12, I075F12 andI075A02) that immunospecifically bind to immobilized BLyS, but not toU937 plasma membranes, TNF-alpha or BSA. As a control, a phage antibodythat recognizes TNFα, is also shown in FIG. 7.

[0048]FIG. 8. The results for two scFvs (I025B09 and I026C04) in areceptor inhibition assay.

[0049]FIG. 9. ELISA results for two scFvs clones (I067F05 and I078D02)demonstrating their ability to bind to immobilized human BLyS and tocross-react with immobilized mouse BLyS, but not to bind to orcross-react with other antigens of the TNF ligand family.

[0050] As a control, a phage antibody that recognizes TNFα, is alsoshown in FIG. 7.

[0051]FIG. 10. Kinetic analysis of scFV antibody I002A01. A dilutionseries of I002A01 from 3 nM to 1650 nM is shown. Association anddissociation curves were generated using a BIAcore 2000 andBIAevaluation 3.0 software.

[0052]FIG. 11. Typical titration curves for two scFvs, I0068C06 andI074B12, are shown in FIG. 11. Unlabelled BLyS competed for binding toits receptor with an inhibitory constant 50 (IC₅₀) value of 0.66 nM. TheIC₅₀ values for I0068C06 and I074B12 are 61 nM and 13 nM, respectively.The assay was performed in triplicate and standard error bars are shown.

[0053]FIG. 12. ELISA results for three clones (I079C01, I081C10 andI082A02) demonstrating their ability to bind histidine-tagged BLyS, U937plasma membranes, but not to bind immobilized biotinylated BLyS.

[0054]FIG. 13. ELISA results for three scFvs (I079B04, I079F08, andI080B01) binding to U937 plasma membranes when either histidine-taggedBLyS or biotinylated BLyS is used as a competitor.

[0055]FIG. 14. An example of the dissociation section of a typicalsensorgram for 8 scFvs is shown in FIG. 14. An anti-TNFα antibody thatdoes not recognize BLyS was included as a control. Of the 8 scFvsexemplified, I079F06 was identified for further study due to therelatively high numbers of RU's bound to the surface.

[0056]FIG. 15. A typical example of the binding curves generated for thescFv antibody I082C03 is shown in FIG. 15. The off-rate for this clonewas calculated as 2×10⁻³ s⁻¹. The affinity of I082C03 was calculated as20 nM, assuming 100% activity of the scFv.

[0057]FIG. 16. ELISA results for three scFvs (I079B04, I079F08, andI080B01) binding to P388 plasma membranes when either histidine-taggedBLyS or biotinylated BLyS is used as a competitor.

DETAILED DESCRIPTION OF THE INVENTION

[0058] The present invention encompasses antibodies (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) that immunospecifically bind to BLyS or a fragment orvariant of BLyS. In particular, the invention provides antibodies suchas, for example, single chain Fvs (scFvs) having an amino acid sequenceof any one of SEQ ID NOS:1-2128, as referred to in Table 1. Inparticular, the present invention encompasses antibodies thatimmunospecifically bind to a polypeptide, a polypeptide fragment orvariant, or an epitope of human BLyS (SEQ ID NOS:3228 and/or 3229) orBLyS expressed on human monocytes; murine BLyS (SEQ ID NOS:3230 and/or3231) or BLyS expressed on murine monocytes; rat BLyS (either thesoluble forms as given in SEQ ID NOS:3232, 3233, 3234 and/or 3235 or ina membrane associated form, e.g., on the surface of rat monocytes); ormonkey BLyS (e.g., the monkey BLyS polypeptides of SEQ ID NOS:3236and/or 3237, the soluble form of monkey BLyS, or BLyS expressed onmonkey monocytes) (as determined by immunoassays known in the art forassaying specific antibody-antigen binding).

[0059] The polypeptide sequence shown in SEQ ID NO:3228 was obtained bysequencing and translating the cDNA of the HNEDU15 clone which wasdeposited on Oct. 22, 1996 at the American Type Culture Collection,10801 University Boulevard, Manassas, Va. 20110-2209, and assigned ATCCAccession No. 97768. The deposited clone is contained in the pBluescriptSK(−) plasmid (Stratagene, La Jolla, Calif.). The ATCC deposits weremade pursuant to the terms of the Budapest Treaty on the internationalrecognition of the deposit of microorganisms for the purposes of patentprocedure.

[0060] The polypeptide sequence shown in SEQ ID NO:3229 was obtained bysequencing and translating the cDNA of the HDPMC52 clone, which wasdeposited on Dec. 10, 1998 at the American Type Culture Collection, andassigned ATCC Accession No. 203518. The deposited clone is contained inthe pBluescript SK(−) plasmid (Stratagene, La Jolla, Calif.). The ATCCdeposits were made pursuant to the terms of the Budapest Treaty on theinternational recognition of the deposit of microorganisms for thepurposes of patent procedure.

[0061] The BLyS polypeptides bound by the antibodies of the inventionmay be in monomers or multimers (i.e., dimers, trimers, tetramers andhigher multimers). Accordingly, the present invention relates toantibodies that bind monomers and multimers of the BLyS polypeptides ofthe invention, their preparation, and compositions (preferably,pharmaceutical compositions) containing them. In specific embodiments,the antibodies of the invention bind BLyS monomers, dimers, trimers ortetramers. In additional embodiments, the antibodies of the inventionbind at least dimers, at least trimers, or at least tetramers of BLyS.

[0062] Multimeric BLyS bound by the antibodies of the invention may behomomers or heteromers. A BLyS homomer, refers to a multimer containingonly BLyS polypeptides (including BLyS fragments, variants, and fusionproteins, as described herein). These homomers may contain BLySpolypeptides having identical or different amino acid sequences. Inspecific embodiments, the antibodies of the invention bind a BLyShomodimer (e.g., containing two BLyS polypeptides having identical ordifferent amino acid sequences) or a BLyS homotrimer (e.g., containingthree BLyS polypeptides having identical or different amino acidsequences). In a preferred embodiment, the antibodies of the inventionbind homotrimers of BLyS. In additional embodiments, the antibodies ofthe invention bind a homomeric BLyS multimer which is at least ahomodimer, at least a homotrimer, or at least a homotetramer.

[0063] Heteromeric BLyS refers to a multimer containing heterologouspolypeptides (i.e., polypeptides of a different protein) in addition tothe BLyS polypeptides of the invention. In a specific embodiment, theantibodies of the invention bind a BLyS heterodimer, a heterotrimer, ora heterotetramer. In additional embodiments, the antibodies of theinvention bind a heteromeric BLyS multimer which is at least aheterodimer, at least a heterotrimer, or at least a heterotetramer. Inhighly preferred embodiments, the antibodies of the invention bind aheterotrimer comprising both BLyS polypeptides and APRIL polypeptides(SEQ ID NO:3239; GenBank Accession No. AF046888; PCT InternationalPublication Number WO97/33902; J. Exp. Med. 188(6):1185-1190) orfragments or variants thereof In other highly preferred embodiments, theantibodies of the invention bind a heterotrimer comprising one BLySpolypeptide (including fragments or variants) and two APRIL polypeptides(including fragments or variants). In still other highly preferredembodiments, the antibodies of the invention bind a heterotrimercomprising two BLyS polypeptides (including fragments or variants) andone APRIIL polypeptide (including fragments or variants). In a furthernonexclusive embodiment, the heteromers bound by the antibodies of theinvention contain CD40 ligand polypeptide sequence(s), or biologicallyactive fragment(s) or variant(s) thereof.

[0064] In particularly preferred embodiments, the antibodies of theinvention bind homomeric, especially homotrimeric, BLyS polypeptides,wherein the individual protein components of the multimers consist ofthe mature form of BLyS (e.g., amino acids residues 134-285 of SEQ IDNO:3228, or amino acids residues 134-266 of SEQ ID NO:3229) or fragmentsor variants thereof. In other specific embodiments, antibodies of theinvention bind heteromeric, especially heterotrimeric, BLyS polypeptidessuch as a heterotrimer containing two BLyS polypeptides and one APRILpolypeptide or a heterotrimer containing one BLyS polypeptide and twoAPRIL polypeptides, and wherein the individual protein components of theBLyS heteromer consist of the mature extracellular soluble portion ofeither BLyS (e.g., amino acids residues 134-285 of SEQ ID NO:3228, oramino acids residues 134-266 of SEQ ID NO:3229) or fragments or variantsthereof, or the mature extracellular soluble portion APRIL (e.g., aminoacid residues 105-250 of SEQ ID NO:3239) or fragments or variantsthereof.

[0065] In specific embodiments, the antibodies of the invention bindconformational epitopes of a BLyS monomeric protein. In specificembodiments, the antibodies of the invention bind conformationalepitopes of a BLyS multimeric, especially trimeric, protein. In otherembodiments, antibodies of the invention bind conformational epitopesthat arise from the juxtaposition of BLyS with a heterologouspolypeptide, such as might be present when BLyS forms heterotrimers(e.g., with APRIL polypeptides (e.g., SEQ ID SEQ ID NO:3239)), or infusion proteins between BLyS and a heterologous polypeptide.

[0066] BLyS multimers bound by the antibodies of the invention may bethe result of hydrophobic, hydrophilic, ionic and/or covalentassociations and/or may be indirectly linked, by for example, liposomeformation. Thus, in one embodiment, BLyS multimers, such as, forexample, homodimers or homotrimers, are formed when polypeptides of theinvention contact one another in solution. In another embodiment, BLySheteromultimers, such as, for example, BLyS heterotrimers or BLySheterotetramers, are formed when polypeptides of the invention contactantibodies to the polypeptides of the invention (including antibodies tothe heterologous polypeptide sequence in a fusion protein of theinvention) in solution. In other embodiments, BLyS multimers are formedby covalent associations with and/or between the BLyS polypeptides ofthe invention. Such covalent associations may involve one or more aminoacid residues contained in the polypeptide sequence (e.g., that recitedin SEQ ID NO:3228 or SEQ ID NO:3229). In one instance, the covalentassociations are cross-linking between cysteine residues located withinthe polypeptide sequences which interact in the native (i.e., naturallyoccurring) polypeptide. In another instance, the covalent associationsare the consequence of chemical or recombinant manipulation.Alternatively, such covalent associations may involve one or more aminoacid residues contained in the heterologous polypeptide sequence in aBLyS fusion protein. In one example, covalent associations are betweenthe heterologous sequence contained in a fusion protein (see, e.g., U.S.Pat. No. 5,478,925). In a specific example, the covalent associationsare between the heterologous sequence contained in a BLyS-Fc fusionprotein. In another specific example, covalent associations of fusionproteins of the invention are between heterologous polypeptide sequencefrom another TNF family ligand/receptor member that is capable offorming covalently associated multimers, such as for example,oseteoprotegerin (see, e.g., International Publication No. WO 98/49305,the contents of which are herein incorporated by reference in itsentirety). In another specific example, covalent associations of fusionproteins of the invention are between heterologous polypeptide sequencefrom CD40L, or a soluble fragment thereof. In another embodiment, two orBLyS polypeptides are joined through synthetic linkers (e.g., peptide,carbohydrate or soluble polymer linkers). Examples include those peptidelinkers described in U.S. Pat. No. 5,073,627 (hereby incorporated byreference). Proteins comprising multiple BLyS polypeptides separated bypeptide linkers may be produced using conventional recombinant DNAtechnology.

[0067] In one embodiment, antibodies of the invention immunospecificallybind a BLyS polypeptide having the amino acid sequence of SEQ ID NO:3228or as encoded by the cDNA clone contained in ATCC No. 97768, or apolypeptide comprising a portion (i.e., a fragment) of the abovepolypeptides. In another embodiment, the invention provides an antibodythat binds an isolated BLyS polypeptide having the amino acid sequenceof SEQ ID NO:3229 or the amino acid sequence encoded by the cDNA clonecontained in ATCC No. 203518, or a an antibody that binds polypeptidecomprising a portion (i.e, fragment) of the above polypeptides.

[0068] Antibodies of the present invention immunospecifically bind topolypeptides comprising or alternatively, consisting of, the amino acidsequence of SEQ ID NO:3228, encoded by the cDNA contained in the plasmidhaving ATCC accession number 97768, or encoded by nucleic acids whichhybridize (e.g., under stringent hybridization conditions) to thenucleotide sequence contained in the deposited clone. Antibodies of thepresent invention also bind to fragments of the amino acid sequence ofSEQ ID NO:3228, encoded by the cDNA contained in the plasmid having ATCCaccession number 97768, or encoded by nucleic acids which hybridize(e.g., under stringent hybridization conditions) to the nucleotidesequence contained in the deposited clone.

[0069] Additionally, antibodies of the present invention bindpolypeptides comprising or alternatively, consisting of, the amino acidsequence of SEQ ID NO:3229, encoded by the cDNA contained in the plasmidhaving ATCC accession number 203518, or encoded by nucleic acids whichhybridize (e.g., under stringent hybridization conditions) to thenucleotide sequence contained in the deposited clone. Antibodies of thepresent invention also bind to fragments of the amino acid sequence ofSEQ ID NO:3229, encoded by the cDNA contained in the plasmid having ATCCaccession number 203518, or encoded by nucleic acids which hybridize(e.g., under stringent hybridization conditions) to the nucleotidesequence contained in the deposited clone.

[0070] In addition, antibodies of the invention bind polypeptides orpolypeptide fragments comprising or alternatively, consisting of, anamino acid sequence contained in SEQ ID NOS: 3230 through 3237.

[0071] In specific embodiments, the antibodies of the present inventionimmunospecifically bind polypeptide fragments including polypeptidescomprising or alternatively, consisting of, an amino acid sequencecontained in SEQ ID NO:3228, encoded by the cDNA contained in thedeposited clone, or encoded by nucleic acids which hybridize (e.g.,under stringent hybridization conditions) to the nucleotide sequencecontained in the deposited clone. Protein fragments may be“free-standing,” or comprised within a larger polypeptide of which thefragment forms a part or region, most preferably as a single continuousregion. Representative examples of polypeptide fragments that may bebound by the antibodies of the present invention, include, for example,fragments that comprise or alternatively, consist of from about aminoacid residues: 1 to 50, 51 to 100, 101 to 150, 151 to 200, 201 to 250,and/or 251 to 285 of SEQ ID NO:3228. Moreover, polypeptide fragments canbe at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,150, 175 or 200 amino acids in length.

[0072] In specific embodiments, antibodies of the present invention bindpolypeptide fragments comprising, or alternatively consisting of, aminoacid residues: 1-46, 31-44, 47-72, 73-285, 73-83, 94-102, 148-152,166-181, 185-209, 210-221, 226-237, 244-249, 253-265, and/or 277-285 ofSEQ ID NO:3228.

[0073] It will be recognized by one of ordinary skill in the art thatmutations targeted to regions of a BLyS polypeptide of SEQ ID NO:3228which encompass the nineteen amino acid residue insertion which is notfound in the BLyS polypeptide sequence of SEQ ID NO:3229 (i.e., aminoacid residues Val-142 through Lys-160 of the sequence of SEQ ID NO:3229)may affect the observed biological activities of the BLyS polypeptide.More specifically, a partial, non-limiting and non-exclusive list ofsuch residues of the BLyS polypeptide sequence which may be targeted formutation includes the following amino acid residues of the BLySpolypeptide sequence as shown in SEQ ID NO:3228: V-142; T-143; Q-144;D-145; C-146; L-147; Q-148; L-149; I-150; A-151; D-152; S-153; E-154;T-155; P-156; T-157; I-158; Q-159; and K-160. Thus, in specificembodiments, antibodies of the present invention that bind BLySpolypeptides which have one or more mutations in the region from V-142through K-160 of SEQ ID NO:3228 are contemplated.

[0074] Polypeptide fragments may be “free-standing,” or comprised withina larger polypeptide of which the fragment forms a part or region, mostpreferably as a single continuous region. Representative examples ofpolypeptide fragments that may be bound by antibodies of the presentinvention, include, for example, fragments that comprise oralternatively, consist of from about amino acid residues: 1 to 15,16-30, 31-46, 47-55, 56-72, 73-104, 105-163, 163-188, 186-210 and210-284 of the amino acid sequence disclosed in SEQ ID NO:3228.Additional representative examples of polypeptide fragments that may bebound by antibodies of the present invention, include, for example,fragments that comprise or alternatively, consist of from about aminoacid residues: 1 to 143, 1-150, 47-143, 47-150, 73-143, 73-150, 100-150,140-145, 142-148, 140-150, 140-200, 140-225, and 140-266 of the aminoacid sequence disclosed in SEQ ID NO:3229. Moreover, polypeptidefragments that may be bound by antibodies of the present invention, canbe at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,150, 175 or 200 amino acids in length. In this context, “about” meansthe particularly recited ranges and ranges larger or smaller by several,a few, 5, 4, 3, 2 or 1 amino acid residues at either or both the amino-and carboxy-termini.

[0075] Additional preferred embodiments encompass antibodies that bindpolypeptide fragments comprising, or alternatively consisting of, thepredicted intracellular domain of BLyS (e.g., amino acid residues 1-46of SEQ ID NO:3228), the predicted transmembrane domain of BLyS (e.g.,amino acid residues 47-72 of SEQ ID NO:3228), the predictedextracellular domain of BLyS (e.g., amino acid residues 73-285 of SEQ IDNO:3228), the mature soluble extracellular domain of BLyS (e.g., aminoacids residues 134-285 of SEQ ID NO:3228), the predicted TNF conserveddomain of BLyS (e.g., amino acids 191 to 284 of SEQ ID NO:3228), and apolypeptide comprising, or alternatively, consisting of the predictedintracellular domain fused to the predicted extracellular domain of BLyS(amino acid residues 1-46 fused to amino acid residues 73-285 of SEQ IDNO:3228).

[0076] Further additional preferred embodiments encompass polypeptidefragments comprising, or alternatively consisting of, the predictedintracellular domain of BLyS (amino acid residues 1-46 of SEQ IDNO:3229), the predicted transmembrane domain of BLyS (amino acidresidues 47-72 of SEQ ID NO:3229), the predicted extracellular domain ofBLyS (amino acid residues 73-266 of SEQ ID NO:3229), the predicted TNFconserved domain of BLyS (amino acids 172 to 265 of SEQ ID NO:3229), anda polypeptide comprising, or alternatively, consisting of the predictedintracellular domain fused to the predicted extracellular domain of BLyS(amino acid residues 1-46 fused to amino acid residues 73-266 of SEQ IDNO:3229).

[0077] Certain additional embodiments of the invention encompassantibodies that bind polypeptide fragments comprising, or alternativelyconsisting of, the predicted beta-pleated sheet regions of the BLySpolypeptides of SEQ ID NO:3228 and SEQ ID NO:3229. These polypeptidefragments comprising the beta-pleated sheets of BLyS comprise, oralternatively consist of, amino acid residues Gln-144 to Ala-151,Phe-172 to Lys-173, Ala-177 to Glu-179, Asn-183 to Ile-185, Gly-191 toLys-204, His-210 to Val-219, Leu-226 to Pro-237, Asn-242 to Ala-251,Gly-256 to Ile-263 and/or Val-276 to Leu-284 of SEQ ID NO:3228. Inanother, nonexclusive embodiment, these polypeptide fragments comprisingthe beta-pleated sheets of BLyS comprise, or alternatively consist of,amino acid residues Phe-153 to Lys-154, Ala-158 to Glu-160, Asn-164 toIle-166, Gly-172 to Lys-185, His-191 to Val-200, Leu-207 to Pro-218,Asn-223 to Ala-232, Gly-237 to Ile-244 and/or Val-257 to Leu-265 of SEQID NO:3229.

[0078] A partial, non-limiting, and exemplary list of polypeptides thatmay be bound by the antibodies of the invention includes polypeptidesthat comprise, or alternatively consist of, combinations of amino acidsequences of the invention includes, for example, [Met-1 to Lys-113]fused to [Leu-114 to Thr-141] fused to [Val-142 to Lys-160] fused to[Gly-161 to Gln-198] fused to [Val-199 to Ala-248] fused to [Gly-249 toLeu-285] of SEQ ID NO:3228; or [Met-1 to Lys-113] fused to [Val-142 toLys-160] fused to [Gly-161 to Gln-198] fused to [Val-199 to Ala-248]fused to [Gly-249 to Leu-285] of SEQ ID NO:3228; or [Met-1 to Lys-113]fused to [Leu-114 to Thr-141] fused to [Val-142 to Lys-160] fused to[Gly-161 to Gln-198] fused to [Gly-249 to Leu-285] of SEQ ID NO:3228.Other combinations of amino acids sequences that may be bound by theantibodies of the invention may include the polypeptide fragments in anorder other than that recited above (e.g., [Leu-114 to Thr-141] fused to[Val-199 to Ala-248] fused to [Gly-249 to Leu-285] fused to [Val-142 toLys-160] of (SEQ ID NO:3228). Other combinations of amino acidssequences that may be bound by the antibodies of the invention may alsoinclude heterologous polypeptide fragments as described herein and/orother polypeptides or polypeptide fragments of the present invention(e.g., [Met-1 to Lys-113] fused to [Leu-114 to Thr-141] fused to[Val-142 to Lys-160] fused to [Gly-161 to Gln-198] fused to [Gly-249 toLeu-285] of SEQ ID NO:3228 fused to a FLAG tag; or [Met-1 to Lys-113] ofSEQ ID NO:3228 fused to [Leu-114 to Thr-141] of SEQ ID NO:3228 fused to[Glu-135 to Asn-165] of SEQ ID NO:39 fused to [Val-142 to Lys-160] ofSEQ ID NO:3228 fused to [Gly-161 to Gln-198] of SEQ ID NO:3228 fused to[Val-199 to Ala-248] of SEQ ID NO:3228 fused to [Gly-249 to Leu-285] ofSEQ ID NO:3228).

[0079] A partial, non-limiting, and exemplary list of polypeptides thatmay be bound by the antibodies of the invention includes polypeptidesthat comprise, or alternatively consist of, combinations of amino acidsequences includes, for example, [Met-1 to Lys-113] fused to [Leu-114 toThr-141] fused to [Gly-142 to Gln-179] fused to [Val-180 to Ala-229]fused to [Gly-230 to Leu-266] of SEQ ID NO:3229; [Met-1 to Lys-113]fused to [Gly-142 to Gln-179] fused to [Val-180 to Ala-229] fused to[Gly-230 to Leu-266] of SEQ ID NO:3229; or [Met-1 to Lys-113] fused to[Leu-114 to Thr-141] fused to [Gly-142 to Gln-179] fused to [Gly-230 toLeu-266] of SEQ ID NO:3229. Other of amino acids sequences that may bebound by the antibodies of the invention combinations may include thepolypeptide fragments in an order other than that recited above (e.g.,[Leu-114 to Thr-141] fused to [Val-180 to Ala-229] fused to [Gly-230 toLeu-266] fused to [Gly-142 to Gln-179] of SEQ ID NO:3229). Othercombinations of amino acid sequences that may be bound by the antibodiesof the invention may also include heterologous polypeptide fragments asdescribed herein and/or other polypeptides or polypeptide fragments ofthe present invention (e.g., [Met-1 to Lys-113] fused to [Leu-114 toThr-141] fused to [Gly-142 to Gln-179] fused to [Gly-230 to Leu-266] ofSEQ ID NO:3229 fused to a FLAG tag (SEQ ID NO:3238) or, [Met-1 toLys-113] of SEQ ID NO:3229 fused to [Leu-114 to Thr-141] of SEQ IDNO:3229 fused to [Glu-135 to Asn-165] of SEQ ID NO:39 fused to [Gly-142to Gln-179] of SEQ ID NO:3229 fused to [Val-180 to Ala-229] of SEQ IDNO:3229 fused to [Gly-230 to Leu-266] of SEQ ID NO:3229.

[0080] Additional embodiments of the invention encompass antibodies thatbind BLyS polypeptide fragments comprising, or alternatively consistingof, functional regions of polypeptides of the invention, such as theGamier-Robson alpha-regions, beta-regions, turn-regions, andcoil-regions, Chou-Fasman alpha-regions, beta-regions, and coil-regions,Kyte-Doolittle hydrophilic regions and hydrophobic regions, Eisenbergalpha- and beta-amphipathic regions, Karplus-Schulz flexible regions,Emini surface-forming regions and Jameson-Wolf regions of high antigenicindex set out in Tables 9 and 10 and as described herein. In a preferredembodiment, the polypeptide fragments bound by the antibodies of theinvention are antigenic (i.e., containing four or more contiguous aminoacids having an antigenic index of greater than or equal to 1.5, asidentified using the default parameters of the Jameson-Wolf program) ofa complete (i.e., full-length) BLyS polypeptide (e.g., SEQ ID NOS:3228and 3229).

[0081] The data representing the structural or functional attributes ofthe BLyS polypeptide of SEQ ID NO:3228 (Table 9) or the BLyS polypeptideof SEQ ID NO:3229 (Table 10), as described above, was generated usingthe various modules and algorithms of the DNA*STAR set on defaultparameters. Column I represents the results of a Garnier-Robson analysisof alpha helical regions; Column II represents the results of aChou-Fasman analysis of alpha helical regions; Column III represents theresults of a Garnier Robson analysis of beta sheet regions; Column IVrepresents the results of a Chou-Fasman analysis of beta sheet regions;Column V represents the results of a Garnier Robson analysis of turnregions; Column VI represents the results of a Chou-Fasman analysis ofturn regions; Column VII represents the results of a Garnier Robsonanalysis of coil regions; Column VIII represents a Kyte-Doolittlehydrophilicity plot; Column IX represents a Hopp-Woods hydrophobicityplot; Column X represents the results of an Eisenberg analysis of alphaamphipathic regions; Column XI represents the results of an Eisenberganalysis of beta amphipathic regions; Column XII represents the resultsof a Karplus-Schultz analysis of flexible regions; Column XIIIrepresents the Jameson-Wolf antigenic index score; and Column XIVrepresents the Emini surface probability plot.

[0082] In a preferred embodiment, the data presented in columns VIII,IX, XIII, and XIV of Tables 9 and 10 can be used to determine regions ofthe BLyS polypeptide of SEQ ID NO:3228 (Table 9) or the BLyS polypeptideof SEQ ID NO:3229 (Table 10) which exhibit a high degree of potentialfor antigenicity. Regions of high antigenicity are determined from thedata presented in columns VIII, IX, XIII, and/or XIV by choosing valueswhich represent regions of the polypeptide which are likely to beexposed on the surface of the polypeptide in an environment in whichantigen recognition may occur in the process of initiation of an immuneresponse.

[0083] The above-mentioned preferred regions set out in Tables 9 and 10include, but are not limited to, regions of the aforementioned typesidentified by analysis of the amino acid sequence set out in SEQ IDNO:2. As set out in Tables 9 and 10, such preferred regions includeGarnier-Robson alpha-regions, beta-regions, turn-regions, andcoil-regions, Chou-Fasman alpha-regions, beta-regions, and turn-regions,Kyte-Doolittle hydrophilic regions, Eisenberg alpha- andbeta-amphipathic regions, Karplus-Schulz flexible regions, Jameson-Wolfregions of high antigenic index and Emini surface-forming regions.Preferably, antibodies of the present invention bind BLyS polypeptidesor BLyS polypeptide fragments and variants comprising regions of BLySthat combine several structural features, such as several (e.g., 1, 2, 3, or 4) of the same or different region features set out above and inTables 9 and 10. TABLE 9 Res Position I II III IV V VI VII VIII IX X XIXII XIII XIV Met 1 A . . . . . . 0.73 −0.71 . . . 0.95 1.39 Asp 2 A . .. . T . 1.12 −0.66 * . . 1.15 1.56 Asp 3 A . . . . T . 1.62 −1.09 * . .1.15 2.12 Ser 4 A . . . . T . 2.01 −1.51 . . . 1.15 4.19 Thr 5 A . . . .T . 2.40 −2.13 . . F 1.30 4.35 Glu 6 A A . . . . . 2.70 −1.73 * * F 0.904.51 Arg 7 A A . . . . . 2.81 −1.34 * * F 0.90 4.51 Glu 8 A A . . . . .2.00 −1.73 * * F 0.90 6.12 Gln 9 A A . . . . . 1.99 −1.53 * * F 0.902.91 Ser 10 A . . B . . . 2.00 −1.04 * * F 0.90 2.15 Arg 11 A . . B . .. 1.33 −0.66 * * F 0.90 1.66 Leu 12 A . . B . . . 0.41 −0.09 * * F 0.450.51 Thr 13 A . . B . . . 0.46 0.20 * * F −0.15 0.32 Ser 14 A A . . . .. 0.50 −0.19 * * . 0.30 0.32 Cys 15 A A . . . . . 0.91 −0.19 * * . 0.300.78 Leu 16 A A . . . . . 0.80 −0.87 * * F 0.90 1.06 Lys 17 A A . . . .. 1.61 −1.36 . * F 0.90 1.37 Lys 18 A A . . . . . 1.32 −1.74 . * F 0.904.44 Arg 19 A A . . . . . 1.67 −1.70 . * F 0.90 5.33 Glu 20 A A . . . .. 1.52 −2.39 . * F 0.90 5.33 Glu 21 A A . . . . . 2.38 −1.70 . * F 0.902.20 Met 22 A A . . . . . 2.33 −1.70 . * F 0.90 2.24 Lys 23 A A . . . .. 1.62 −1.70 * * F 0.90 2.24 Leu 24 A A . . . . . 0.66 −1.13 * * F 0.750.69 Lys 25 A A . . . . . 0.36 −0.49 . * F 0.45 0.52 Glu 26 A A . B . .. −0.53 −0.71 * * . 0.60 0.35 Cys 27 A A . B . . . −0.74 −0.03 * * .0.30 0.30 Val 28 A A . B . . . −1.00 −0.03 * * . 0.30 0.12 Ser 29 A A .B . . . −0.08 0.40 * * . −0.30 0.11 Ile 30 A . . B . . . −0.08 0.40 * *. −0.30 0.40 Leu 31 A . . B . . . −0.08 −0.17 * . . 0.45 1.08 Pro 32 . .. B . . C 0.29 −0.81 * . F 1.10 1.39 Arg 33 . . . . T . . 0.93 −0.81 . *F 1.50 2.66 Lys 34 . . . . T . . 0.93 −1.07 . . F 1.84 4.98 Glu 35 . . .. . . C 0.97 −1.37 * * F 1.98 4.32 Ser 36 . . . . . T C 1.89 −1.16 * * F2.52 1.64 Pro 37 . . . . . T C 1.80 −1.16 * * F 2.86 1.60 Ser 38 . . . .T T . 1.39 −0.77 * . F 3.40 1.24 Val 39 A . . . . T . 1.39 −0.39 . * F2.36 1.24 Arg 40 A . . . . . . 1.39 −0.77 * * F 2.46 1.60 Ser 41 A . . .. . . 1.34 −1.20 * * F 2.46 2.00 Ser 42 . . . . T T . 1.60 −1.16 . * F3.06 2.67 Lys 43 . . . . T T . 1.09 −1.80 . * F 3.06 2.72 Asp 44 . . . .T T . 1.13 −1.11 * * F 3.40 1.67 Gly 45 A . . . . T . 0.43 −0.81 * * F2.66 1.03 Lys 46 A A . . . . . 0.14 −0.70 . . F 1.77 0.52 Leu 47 A A . .. . . 0.13 −0.20 * . . 0.98 0.31 Leu 48 A A . . . . . −0.72 0.29 * . .0.04 0.46 Ala 49 A A . . . . . −1.53 0.54 . * . −0.60 0.19 Ala 50 A A .. . . . −2.00 1.23 . . . −0.60 0.19 Thr 51 A A . . . . . −2.63 1.23 . .. −0.60 0.19 Leu 52 A A . . . . . −2.63 1.04 . . . −0.60 0.19 Leu 53 A A. . . . . −2.63 1.23 . . . −0.60 0.15 Leu 54 A A . . . . . −2.34 1.41 .. . −0.60 0.09 Ala 55 A A . . . . . −2.42 1.31 . . . −0.60 0.14 Leu 56 AA . . . . . −2.78 1.20 . . . −0.60 0.09 Leu 57 A . . . . T . −2.78 1.09. . . −0.20 0.06 Ser 58 A . . . . T . −2.28 1.09 . . . −0.20 0.05 Cys 59A . . . . T . −2.32 1.07 . . . −0.20 0.09 Cys 60 A . . . . T . −2.591.03 . . . −0.20 0.08 Leu 61 . . B B . . . −2.08 0.99 . . . −0.60 0.04Thr 62 . . B B . . . −1.97 0.99 . . . −0.60 0.11 Val 63 . . B B . . .−1.91 1.20 . . . −0.60 0.17 Val 64 . . B B . . . −1.24 1.39 . . . −0.600.33 Ser 65 . . B B . . . −1.43 1.10 . . . −0.60 0.40 Phe 66 A . . B . .. −1.21 1.26 . . . −0.60 0.40 Tyr 67 A . . B . . . −1.49 1.11 . . .−0.60 0.54 Gln 68 A . . B . . . −1.44 0.97 . . . −0.60 0.41 Val 69 A . .B . . . −0.59 1.27 . . . −0.60 0.39 Ala 70 A . . B . . . −0.63 0.89 . .. −0.60 0.43 Ala 71 A . . B . . . 0.07 0.56 . * . −0.60 0.25 Leu 72 A .. . . T . −0.50 0.16 . * . 0.10 0.55 Gln 73 A . . . . T . −1.09 0.20 . .F 0.25 0.45 Gly 74 A . . . . T . −0.53 0.20 . . F 0.25 0.45 Asp 75 A . .. . T . −0.76 0.09 . * F 0.25 0.73 Leu 76 A A . . . . . −0.06 0.09 . * F−0.15 0.35 Ala 77 A A . . . . . 0.17 −0.31 . * . 0.30 0.69 Ser 78 A A .. . . . 0.17 −0.24 . * . 0.30 0.42 Leu 79 A A . . . . . −0.30 −0.24 . *. 0.30 0.88 Arg 80 A A . . . . . −0.30 −0.24 . * . 0.30 0.72 Ala 81 A A. . . . . 0.17 −0.34 . * . 0.30 0.93 Glu 82 A A . . . . . 0.72 −0.30 . *. 0.45 1.11 Leu 83 A A . . . . . 0.99 −0.49 . * . 0.30 0.77 Gln 84 A A .. . . . 1.21 0.01 . * . −0.15 1.04 Gly 85 A A . . . . . 1.10 0.01 * * .−0.30 0.61 His 86 A A . . . . . 1.73 0.01 * * . −0.15 1.27 His 87 A A .. . . . 0.92 −0.67 . * . 0.75 1.47 Ala 88 A A . . . . . 1.52 −0.39 . * .0.45 1.22 Glu 89 A A . . . . . 0.93 −0.39 . . . 0.45 1.39 Lys 90 A A . .. . . 0.93 −0.39 * . F 0.60 1.03 Leu 91 A . . . . T . 0.38 −0.46 * . .0.85 1.01 Pro 92 A . . . . T . 0.07 −0.46 . . . 0.70 0.59 Ala 93 A . . .. T . 0.07 −0.03 . . . 0.70 0.29 Gly 94 A . . . . T . −0.14 0.47 . . .−0.20 0.36 Ala 95 A . . . . . . −0.14 0.21 . * . −0.10 0.36 Gly 96 A . .. . . . 0.08 −0.21 . . F 0.65 0.71 Ala 97 A . . . . . . −0.06 −0.21 . .F 0.65 0.72 Pro 98 A . . . . . . −0.28 −0.21 . * F 0.65 0.71 Lys 99 A A. . . . . 0.07 −0.03 . . F 0.45 0.59 Ala 100 A A . . . . . 0.66 −0.46 .. F 0.60 1.01 Gly 101 A A . . . . . 0.41 −0.96 . . F 0.90 1.13 Leu 102 AA . . . . . 0.79 −0.89 . . F 0.75 0.57 Glu 103 A A . . . . . 0.41−0.46 * . F 0.45 0.88 Glu 104 A A . . . . . −0.49 −0.46 * . F 0.45 0.89Ala 105 A A . . . . . −0.21 −0.24 . . . 0.30 0.81 Pro 106 A A . . . . .−0.46 −0.44 . . . 0.30 0.67 Ala 107 A A . . . . . 0.01 0.06 . . . −0.300.39 Val 108 A A . . . . . −0.80 0.49 . * . −0.60 0.38 Thr 109 A A . . .. . −0.76 0.67 . * . −0.60 0.20 Ala 110 A A . . . . . −1.06 0.24 * * .−0.30 0.40 Gly 111 A A . . . . . −1.54 0.43 * * . −0.60 0.38 Leu 112 A A. . . . . −0.96 0.57 * * . −0.60 0.23 Lys 113 . A B . . . . −0.310.09 * * . −0.30 0.39 Ile 114 . A B . . . . −0.21 0.01 * . . −0.30 0.61Phe 115 . A B . . . . −0.21 0.01 * . . 0.15 1.15 Glu 116 . A . . . . C−0.08 −0.17 * . F 1.25 0.58 Pro 117 . A . . . . C 0.39 0.26 * * F 1.101.28 Pro 118 . . . . . . C 0.34 −0.00 . . F 2.20 1.47 Ala 119 . . . . .T C 0.89 −0.79 . * F 3.00 1.47 Pro 120 . . . . . T C 1.59 −0.36 . * F2.25 0.94 Gly 121 . . . . T T . 1.29 −0.39 . * F 2.15 0.98 Glu 122 . . .. T T . 1.20 −0.43 . . F 2.00 1.30 Gly 123 . . . . . . C 1.41 −0.54 . .F 1.60 1.12 Asn 124 . . . . . T C 2.00 −0.57 . . F 1.50 1.97 Ser 125 . .. . . T C 1.91 −0.60 . * F 1.50 1.82 Ser 126 . . . . . T C 2.37 −0.21. * F 1.54 2.47 Gln 127 . . . . . T C 2.37 −0.64 . * F 2.18 3.01 Asn 128. . . . . . C 2.76 −0.64 . . F 2.32 3.61 Ser 129 . . . . . T C 2.87−1.03 . . F 2.86 5.39 Arg 130 . . . . T T . 2.58 −1.41 * . F 3.40 6.09Asn 131 . . . . T T . 2.02 −1.31 * . F 3.06 3.83 Lys 132 . . . . T T .2.02 −1.07 * . F 2.72 2.12 Arg 133 . . . . T . . 1.68 −1.06 * . F 2.181.88 Ala 134 . . . . . . C 1.77 −0.63 * . F 1.64 1.15 Val 135 . . . . .. C 1.66 −0.60 * . F 1.49 0.89 Gln 136 . . . . . . C 1.66 −0.60 * . F1.83 0.79 Gly 137 . . . . . T C 1.30 −0.60 * . F 2.52 1.35 Pro 138 . . .. . T C 0.33 −0.61 * . F 2.86 2.63 Glu 139 . . . . T T . 0.61 −0.61 * .F 3.40 1.13 Glu 140 A . . . . T . 1.47 −0.53 * . F 2.66 1.64 Thr 141 A .. . . . . 1.47 −0.56 . . F 2.12 1.84 Val 142 A . . . . . . 1.14 −0.99 .. F 1.78 1.77 Thr 143 A . . . . T . 0.54 −0.41 . . F 1.19 0.55 Gln 144 A. . . . T . 0.54 0.27 * . F 0.25 0.31 Asp 145 A . . . . T . −0.27 0.19 *. F 0.25 0.73 Cys 146 A . . . . T . −0.84 0.23 * . . 0.10 0.42 Leu 147 AA . . . . . −0.58 0.43 * . . −0.60 0.17 Gln 148 A A . . . . . −0.270.53 * . . −0.60 0.10 Leu 149 A A . . . . . −0.57 0.53 * * . −0.30 0.32Ile 150 A A . . . . . −0.57 0.34 * . . 0.30 0.52 Ala 151 . A . . . . C−0.21 −0.34 . * . 1.40 0.52 Asp 152 . . . . T T . 0.39 −0.26 . * F 2.450.91 Ser 153 . . . . . T C 0.08 −0.51 . . F 3.00 2.00 Glu 154 . . . . .T C −0.00 −0.71 . . F 2.70 2.86 Thr 155 . . . . . T C 0.89 −0.53 * . F2.40 1.20 Pro 156 . . . B . . C 1.52 −0.13 * . F 1.56 1.55 Thr 157 . . .B T . . 1.18 −0.51 * . F 1.92 1.79 Ile 158 A . . B . . . 1.18 −0.09 . .F 1.08 1.23 Gln 159 . . . . T T . 0.93 −0.19 . . F 2.04 1.07 Lys 160 . .. . T T . 0.93 0.14 * . F 1.60 1.16 Gly 161 . . . . T T . 0.44 0.14 * .F 1.44 2.38 Ser 162 . . . . T T . −0.10 0.24 * . F 1.28 1.19 Tyr 163 . .. B T . . 0.58 0.49 * . . 0.12 0.44 Thr 164 . . B B . . . 0.29 0.91 * .. −0.44 0.69 Phe 165 . . B B . . . −0.57 1.40 * . . −0.60 0.54 Val 166 .. B B . . . −1.03 1.70 . . . −0.60 0.29 Pro 167 . . B B . . . −1.03 1.63. . . −0.60 0.16 Trp 168 A . . B . . . −1.49 1.53 . * . −0.60 0.25 Leu169 A . . B . . . −1.13 1.53 * . . −0.60 0.29 Leu 170 A . . B . . .−0.32 0.89 * . . −0.30 0.38 Ter 171 A . . . . . . 0.19 0.46 * . . 0.200.71 Phe 172 . . . . T . . 0.10 −0.03 * . . 1.80 0.85 Lys 173 . . . . TT . −0.20 −0.33 * . F 2.60 1.38 Arg 174 . . . . . T C −0.20 −0.51 . . F3.00 1.04 Gly 175 . . . . . T C 0.61 −0.21 . . F 2.25 0.99 Ser 176 A . .. . T . 0.91 −1.00 * . F 2.05 0.86 Ala 177 A A . . . . . 1.66 −1.00 * .F 1.35 0.76 Leu 178 A A . . . . . 1.61 −1.00 . . F 1.20 1.54 Glu 179 A A. . . . . 1.50 −1.43 . . F 0.90 1.98 Glu 180 A A . . . . . 1.89 −1.41 *. F 0.90 3.16 Lys 181 A A . . . . . 1.30 −1.91 * . F 0.90 7.66 Glu 182 AA . . . . . 1.08 −1.91 . . F 0.90 3.10 Asn 183 A A . . . . . 1.03−1.23 * * F 0.90 1.48 Lys 184 A A . . . . . 1.08 −0.59 * . F 0.75 0.55Ile 185 A A . . . . . 1.08 −0.59 * * . 0.60 0.63 Leu 186 A A . . . . .0.72 −0.59 * * . 0.60 0.68 Val 187 A A . . . . . 0.38 −0.50 . * . 0.300.49 Lys 188 A A . . . . . 0.13 −0.07 * * F 0.45 0.69 Glu 189 A . . . .T . −0.61 0.00 * * F 0.40 1.32 Thr 190 . . . . T T . −0.42 0.10 . * F0.80 1.54 Gly 191 . . . . T T . −0.50 0.24 * . F 0.65 0.67 Tyr 192 . . .. T T . 0.11 0.93 * * . 0.20 0.27 Phe 193 . . B B . . . −0.28 1.69 . . .−0.60 0.29 Phe 194 . . B B . . . −0.28 1.63 . * . −0.60 0.29 Ile 195 . .B B . . . −0.82 1.60 . . . −0.60 0.32 Tyr 196 . . B B . . . −1.29 1.49 .. . −0.60 0.28 Gly 197 . . . B T . . −1.29 1.39 . . . −0.20 0.26 Gln 198. . . B T . . −0.90 1.36 . . . −0.20 0.59 Val 199 . . . B . . C −0.201.16 . . . −0.40 0.54 Leu 200 . . . B . . C 0.73 0.40 . . . −0.10 0.92Tyr 201 . . . . T T . 0.67 −0.03 . . . 1.25 1.06 Thr 202 . . . . T T .0.77 0.06 . . F 0.80 2.06 Asp 203 . . . . T T . 0.18 0.17 . . F 0.803.91 Lys 204 A . . . . T . 0.43 −0.01 . . F 1.00 2.52 Thr 205 A A . . .. . 0.90 −0.16 . . F 0.60 1.73 Tyr 206 A A . . . . . 1.11 −0.21 . . .0.45 1.03 Ala 207 A A . . . . . 0.61 0.29 . . . −0.30 0.70 Met 208 A A .. . . . −0.28 0.97 . . . −0.60 0.40 Gly 209 A A . B . . . −0.32 1.17 * .. −0.60 0.18 His 210 A A . B . . . 0.10 0.81 * . . −0.60 0.31 Leu 211 AA . B . . . 0.39 0.31 . . . −0.30 0.61 Ile 212 A A . B . . . 1.02 −0.30. . . 0.45 1.22 Gln 213 A A . B . . . 0.77 −0.73 . * . 0.75 1.80 Arg 214A A . B . . . 1.08 −0.59 . * F 0.90 1.62 Lys 215 A A . B . . . 0.26−0.77 * * F 0.90 3.14 Lys 216 A A . B . . . 0.37 −0.81 . * F 0.90 1.35Val 217 . A B B . . . 0.91 −0.43 * * . 0.30 0.60 His 218 . A B B . . .0.91 −0.00 . * . 0.30 0.29 Val 219 . A B B . . . 0.80 −0.00 * * . 0.300.25 Phe 220 . . B B . . . −0.06 −0.00 * . . 0.30 0.57 Gly 221 A . . B .. . −0.40 0.04 . * . −0.30 0.35 Asp 222 A . . . . . . −0.36 −0.07 * . .0.50 0.63 Glu 223 A . . . . . . −1.18 −0.03 * . . 0.50 0.60 Leu 224 A .. B . . . −0.63 −0.17 . . . 0.30 0.45 Ser 225 A . . B . . . −0.74 −0.11. . . 0.30 0.39 Leu 226 A . . B . . . −1.10 0.57 . * . −0.60 0.18 Val227 A . . B . . . −0.99 1.36 . * . −0.60 0.19 Thr 228 A . . B . . .−1.66 0.67 * * . −0.60 0.28 Leu 229 A . . B . . . −1.73 0.86 * . . −0.600.18 Phe 230 A . . B . . . −1.43 0.86 * . . −0.60 0.17 Arg 231 A . . B .. . −0.62 0.61 * . . −0.60 0.21 Cys 232 . . . B T . . −0.37 0.53 * . .−0.20 0.41 Ile 233 . . . B T . . −0.27 0.46 * . . −0.20 0.46 Gln 234 . .. B T . . 0.54 0.10 * . . 0.10 0.37 Asn 235 . . . B . . C 0.93 0.10 * .. 0.05 1.19 Met 236 . . . B . . C 0.01 0.01 * . F 0.20 2.44 Pro 237 . .. B . . C 0.47 0.01 * . F 0.44 1.16 Glu 238 . . . . T . . 1.36 0.04 * .F 1.08 1.12 Thr 239 . . . . . . C 1.36 0.04 * . F 1.12 1.82 Leu 240 . .. . . . C 1.06 −0.17 * . F 1.96 1.89 Pro 241 . . . . T . . 0.99 −0.21 .. F 2.40 1.46 Asn 242 . . . . T . . 0.96 0.36 . . F 1.41 0.54 Asn 243 .. . . T T . 0.66 0.63 . . F 1.22 1.03 Ser 244 . . . . T T . 0.38 0.33 .. F 1.13 0.89 Cys 245 . . . . T T . 0.84 0.40 . . . 0.74 0.56 Tyr 246 .. . . T T . 0.17 0.43 . . . 0.20 0.35 Ser 247 A . . . . . . −0.42 0.71 .. . −0.40 0.18 Ala 248 A A . . . . . −0.38 0.83 . . . −0.60 0.34 Gly 249A A . . . . . −0.89 0.26 . . . −0.30 0.43 Ile 250 A A . . . . . −0.220.19 * . . −0.30 0.27 Ala 251 A A . . . . . 0.02 −0.20 * . . 0.30 0.46Lys 252 A A . . . . . −0.02 −0.70 . . . 0.60 0.80 Leu 253 A A . . . . .0.57 −0.70 . . F 0.90 1.13 Glu 254 A A . . . . . 0.91 −1.39 . . F 0.901.87 Glu 255 A A . . . . . 0.99 −1.89 . . F 0.90 1.62 Gly 256 A A . . .. . 1.58 −1.20 . * F 0.90 1.62 Asp 257 A A . . . . . 0.72 −1.49 . * F0.90 1.62 Glu 258 A A . . . . . 0.94 −0.80 * * F 0.75 0.77 Leu 259 A A .. . . . 0.06 −0.30 * * . 0.30 0.79 Gln 260 A A . . . . . −0.16 −0.04 * .. 0.30 0.33 Leu 261 A A . . . . . 0.30 0.39 * . . −0.30 0.30 Ala 262 A A. . . . . 0.30 0.39 * . . −0.30 0.70 Ile 263 A A . . . . . 0.30 −0.30. * . 0.30 0.70 Pro 264 A . . . . T . 0.52 −0.30 . * F 1.00 1.37 Arg 265A . . . . T . 0.52 −0.49 . * F 1.00 1.37 Glu 266 A . . . . T . 0.44−0.59 * * F 1.30 3.38 Asn 267 A . . . . T . 0.73 −0.59 * * F 1.30 1.53Ala 268 A . . . . . . 0.81 −0.63 * * . 0.95 1.05 Gln 269 A . . . . . .1.02 0.06 * * . −0.10 0.50 Ile 270 A . . . . . . 0.57 0.06 . * . 0.150.52 Ser 271 . . . . . . C 0.57 0.09 . * . 0.60 0.51 Leu 272 . . . . . .C −0.29 −0.41 . * F 1.60 0.49 Asp 273 . . . . T T . −0.01 −0.17 . * F2.25 0.52 Gly 274 . . . . T T . −0.71 −0.37 . * F 2.50 0.56 Asp 275 . .. . T T . −0.52 0.03 . * F 1.65 0.59 Val 276 A . . . . T . −0.57 0.13. * F 1.00 0.30 Thr 277 A . . B . . . −0.34 0.56 . * . −0.10 0.30 Phe278 A . . B . . . −1.16 0.63 . * . −0.35 0.18 Phe 279 A . . B . . .−0.77 1.31 . * . −0.60 0.20 Gly 280 A A . . . . . −1.58 0.67 . * . −0.600.28 Ala 281 A A . . . . . −1.53 0.87 . * . −0.60 0.27 Leu 282 A A . . .. . −1.61 0.77 * . . −0.60 0.26 Lys 283 A A . . . . . −1.30 0.41 * . .−0.60 0.33 Leu 284 A A . . . . . −0.99 0.41 . . . −0.60 0.42 Leu 285 A A. . . . . −1.03 0.34 * . . −0.30 0.65

[0084] TABLE 10 Res Position I II III IV V VI VII VIII IX X XI XII XIIIXIV Met 1 A . . . . . . 0.73 −0.71 . . . 0.95 1.39 Asp 2 A . . . . T .1.12 −0.66 * . . 1.15 1.56 Asp 3 A . . . . T . 1.62 −1.09 * . . 1.152.12 Ser 4 A . . . . T . 2.01 −1.51 . . . 1.15 4.19 Thr 5 A . . . . T .2.40 −2.13 . . F 1.30 4.35 Glu 6 A A . . . . . 2.70 −1.73 * * F 0.904.51 Arg 7 A A . . . . . 2.81 −1.34 * * F 0.90 4.51 Glu 8 A A . . . . .2.00 −1.73 * * F 0.90 6.12 Gln 9 A A . . . . . 1.99 −1.53 * * F 0.902.91 Ser 10 A . . B . . . 2.00 −1.04 * * F 0.90 2.15 Arg 11 A . . B . .. 1.33 −0.66 * * F 0.90 1.66 Leu 12 A . . B . . . 0.41 −0.09 * * F 0.450.51 Thr 13 A . . B . . . 0.46 0.20 * * F −0.15 0.32 Ser 14 A A . . . .. 0.50 −0.19 * * . 0.30 0.32 Cys 15 A A . . . . . 0.91 −0.19 * * . 0.300.78 Leu 16 A A . . . . . 0.80 −0.87 * * F 0.90 1.06 Lys 17 A A . . . .. 1.61 −1.36 . * F 0.90 1.37 Lys 18 A A . . . . . 1.32 −1.74 . * F 0.904.44 Arg 19 A A . . . . . 1.67 −1.70 . * F 0.90 5.33 Glu 20 A A . . . .. 1.52 −2.39 . * F 0.90 5.33 Glu 21 A A . . . . . 2.38 −1.70 . * F 0.902.20 Met 22 A A . . . . . 2.33 −1.70 . * F 0.90 2.24 Lys 23 A A . . . .. 1.62 −1.70 * * F 0.90 2.24 Leu 24 A A . . . . . 0.66 −1.13 * * F 0.750.69 Lys 25 A A . . . . . 0.36 −0.49 . * F 0.45 0.52 Glu 26 A A . B . .. −0.53 −0.71 * * . 0.60 0.35 Cys 27 A A . B . . . −0.74 −0.03 * * .0.30 0.30 Val 28 A A . B . . . −1.00 −0.03 * * . 0.30 0.12 Ser 29 A A .B . . . −0.08 0.40 * * . −0.30 0.11 Ile 30 A . . B . . . −0.08 0.40 * *. −0.30 0.40 Leu 31 A . . B . . . −0.08 −0.17 * . . 0.45 1.08 Pro 32 . .. B . . C 0.29 −0.81 * . F 1.10 1.39 Arg 33 . . . . T . . 0.93 −0.81 . *F 1.50 2.66 Lys 34 . . . . T . . 0.93 −1.07 . . F 1.84 4.98 Glu 35 . . .. . . C 0.97 −1.37 * * F 1.98 4.32 Ser 36 . . . . . T C 1.89 −1.16 * * F2.52 1.64 Pro 37 . . . . . T C 1.80 −1.16 * * F 2.86 1.60 Ser 38 . . . .T T . 1.39 −0.77 * . F 3.40 1.24 Val 39 A . . . . T . 1.39 −0.39 . * F2.36 1.24 Arg 40 A . . . . . . 1.39 −0.77 * * F 2.46 1.60 Ser 41 A . . .. . . 1.34 −1.20 * * F 2.46 2.00 Ser 42 . . . . T T . 1.60 −1.16 . * F3.06 2.67 Lys 43 . . . . T T . 1.09 −1.80 * * F 3.06 2.72 Asp 44 . . . .T T . 1.13 −1.11 * * F 3.40 1.67 Gly 45 A . . . . T . 0.43 −0.81 * * F2.66 1.03 Lys 46 A A . . . . . 0.14 −0.70 . . F 1.77 0.52 Leu 47 A A . .. . . 0.13 −0.20 * . . 0.98 0.31 Leu 48 A A . . . . . −0.72 0.29 * . .0.04 0.46 Ala 49 A A . . . . . −1.53 0.54 . * . −0.60 0.19 Ala 50 A A .. . . . −2.00 1.23 . . . −0.60 0.19 Thr 51 A A . . . . . −2.63 1.23 . .. −0.60 0.19 Leu 52 A A . . . . . −2.63 1.04 . . . −0.60 0.19 Leu 53 A A. . . . . −2.63 1.23 . . . −0.60 0.15 Leu 54 A A . . . . . −2.34 1.41 .. . −0.60 0.09 Ala 55 A A . . . . . −2.42 1.31 . . . −0.60 0.14 Leu 56 AA . . . . . −2.78 1.20 . . . −0.60 0.09 Leu 57 A . . . . T . −2.78 1.09. . . −0.20 0.06 Ser 58 A . . . . T . −2.28 1.09 . . . −0.20 0.05 Cys 59A . . . . T . −2.32 1.07 . . . −0.20 0.09 Cys 60 A . . . . T . −2.591.03 . . . −0.20 0.08 Leu 61 . . B B . . . −2.08 0.99 . . . −0.60 0.04Thr 62 . . B B . . . −1.97 0.99 . . . −0.60 0.11 Val 63 . . B B . . .−1.91 1.20 . . . −0.60 0.17 Val 64 . . B B . . . −1.24 1.39 . . . −0.600.33 Ser 65 . . B B . . . −1.43 1.10 . . . −0.60 0.40 Phe 66 A . . B . .. −1.21 1.26 . . . −0.60 0.40 Tyr 67 A . . B . . . −1.49 1.11 . . .−0.60 0.54 Gln 68 A . . B . . . −1.44 0.97 . . . −0.60 0.41 Val 69 A . .B . . . −0.59 1.27 . . . −0.60 0.39 Ala 70 A . . B . . . −0.63 0.89 . .. −0.60 0.43 Ala 71 A . . B . . . 0.07 0.56 . * . −0.60 0.25 Leu 72 A .. . . T . −0.50 0.16 . . . 0.10 0.55 Gln 73 A . . . . T . −1.09 0.20 . .F 0.25 0.45 Gly 74 A . . . . T . −0.53 0.20 . . F 0.25 0.45 Asp 75 A . .. . T . −0.76 0.09 . * F 0.25 0.73 Leu 76 A A . . . . . −0.06 0.09 . * F−0.15 0.35 Ala 77 A A . . . . . 0.17 −0.31 . * . 0.30 0.69 Ser 78 A A .. . . . 0.17 −0.24 . * . 0.30 0.42 Leu 79 A A . . . . . −0.30 −0.24 . *. 0.30 0.88 Arg 80 A A . . . . . −0.30 −0.24 . * . 0.30 0.72 Ala 81 A A. . . . . 0.17 −0.34 . * . 0.30 0.93 Glu 82 A A . . . . . 0.72 −0.30 . *. 0.45 1.11 Leu 83 A A . . . . . 0.99 −0.49 . * . 0.30 0.77 Gln 84 A A .. . . . 1.21 0.01 . * . −0.15 1.04 Gly 85 A A . . . . . 1.10 0.01 * * .−0.30 0.61 His 86 A A . . . . . 1.73 0.01 * * . −0.15 1.27 His 87 A A .. . . . 0.92 −0.67 . * . 0.75 1.47 Ala 88 A A . . . . . 1.52 −0.39 . * .0.45 1.22 Glu 89 A A . . . . . 0.93 −0.39 . . . 0.45 1.39 Lys 90 A A . .. . . 0.93 −0.39 * . F 0.60 1.03 Leu 91 A . . . . T . 0.38 −0.46 * . .0.85 1.01 Pro 92 A . . . . T . 0.07 −0.46 . . . 0.70 0.59 Ala 93 A . . .. T . 0.07 −0.03 . . . 0.70 0.29 Gly 94 A . . . . T . −0.14 0.47 . . .−0.20 0.36 Ala 95 A . . . . . . −0.14 0.21 . * . −0.10 0.36 Gly 96 A . .. . . . 0.08 −0.21 . . F 0.65 0.71 Ala 97 A . . . . . . −0.06 −0.21 . .F 0.65 0.72 Pro 98 A . . . . . . −0.28 −0.21 . * F 0.65 0.71 Lys 99 A A. . . . . 0.07 −0.03 . . F 0.45 0.59 Ala 100 A A . . . . . 0.66 −0.46 .. F 0.60 1.01 Gly 101 A A . . . . . 0.41 −0.96 . . F 0.90 1.13 Leu 102 AA . . . . . 0.79 −0.89 . . F 0.75 0.57 Glu 103 A A . . . . . 0.41−0.46 * . F 0.45 0.88 Glu 104 A A . . . . . −0.49 −0.46 * . F 0.45 0.89Ala 105 A A . . . . . −0.21 −0.24 . . . 0.30 0.81 Pro 106 A A . . . . .−0.46 −0.44 . . . 0.30 0.67 Ala 107 A A . . . . . 0.01 0.06 . . . −0.300.39 Val 108 A A . . . . . −0.80 0.49 * * . −0.60 0.38 Thr 109 A A . . .. . −0.76 0.67 . * . −0.60 0.20 Ala 110 A A . . . . . −1.06 0.24 * * .−0.30 0.40 Gly 111 A A . . . . . −1.54 0.43 * * . −0.60 0.38 Leu 112 A A. . . . . −0.96 0.57 * * . −0.60 0.23 Lys 113 . A B . . . . −0.310.09 * * . −0.30 0.39 Ile 114 . A B . . . . −0.21 0.01 * . . −0.30 0.61Phe 115 . A B . . . . −0.21 0.01 * . . 0.15 1.15 Glu 116 . A . . . . C−0.08 −0.17 * . F 1.25 0.58 Pro 117 . A . . . . C 0.39 0.26 * * F 1.101.28 Pro 118 . . . . . . C 0.34 0.00 * . F 2.20 1.47 Ala 119 . . . . . TC 0.89 −0.79 . * F 3.00 1.47 Pro 120 . . . . . T C 1.59 −0.36 . * F 2.250.94 Gly 121 . . . . T T . 1.29 −0.39 . * F 2.15 0.98 Glu 122 . . . . TT . 1.20 −0.43 . . F 2.00 1.30 Gly 123 . . . . . . C 1.41 −0.54 . . F1.60 1.12 Asn 124 . . . . . T C 2.00 −0.57 . . F 1.50 1.97 Ser 125 . . .. . T C 1.91 −0.60 . * F 1.50 1.82 Ser 126 . . . . . T C 2.37 −0.21 . *F 1.54 2.47 Gln 127 . . . . . T C 2.37 −0.64 . * F 2.18 3.01 Asn 128 . .. . . . C 2.76 −0.64 . . F 2.32 3.61 Ser 129 . . . . . T C 2.87 −1.03 .. F 2.86 5.39 Arg 130 . . . . T T . 2.58 −1.41 * . F 3.40 6.09 Asn 131 .. . . T T . 2.02 −1.31 * . F 3.06 3.83 Lys 132 . . . . T T . 2.02−1.07 * . F 2.72 2.12 Arg 133 . . . . T . . 1.68 −1.06 * . F 2.18 1.88Ala 134 . . . . . . C 1.77 −0.63 * . F 1.64 1.15 Val 135 . . . . . . C1.66 −0.60 * . F 1.15 0.89 Gln 136 . . . . . . C 1.66 −0.60 * . F 1.490.79 Gly 137 . . . . . T C 1.30 −0.60 * . F 2.18 1.35 Pro 138 . . . . .T C 0.84 −0.61 * . F 2.52 2.63 Glu 139 . . . . . T C 1.13 −0.83 * . F2.86 1.50 Glu 140 . . . . T T . 1.74 −0.84 . . F 3.40 2.03 Thr 141 . . .. T . . 1.43 −0.51 . . F 2.86 2.06 Gly 142 . . . . T T . 1.08 −0.46 . .F 2.42 1.72 Ser 143 . . . . T T . 0.43 0.33 . . F 1.33 0.86 Tyr 144 . .. . T T . 0.22 0.97 . . . 0.54 0.44 Thr 145 . . . . T T . −0.07 0.91 . .. 0.20 0.69 Phe 146 . . B B . . . −0.57 1.40 . . . −0.60 0.54 Val 147 .. B B . . . −1.03 1.70 . . . −0.60 0.29 Pro 148 . . B B . . . −1.03 1.63. . . −0.60 0.16 Trp 149 A . . B . . . −1.49 1.53 . * . −0.60 0.25 Leu150 A . . B . . . −1.13 1.53 * . . −0.60 0.29 Leu 151 A . . B . . .−0.32 0.89 * . . −0.30 0.38 Ser 152 A . . . . . . 0.19 0.46 * . . 0.200.71 Phe 153 . . . . T . . 0.10 −0.03 * . . 1.80 0.85 Lys 154 . . . . TT . −0.20 −0.33 * . F 2.60 1.38 Arg 155 . . . . . T C −0.20 −0.51 . . F3.00 1.04 Gly 156 . . . . . T C 0.61 −0.21 . . F 2.25 0.99 Ser 157 A . .. . T . 0.91 −1.00 * . F 2.05 0.86 Ala 158 A A . . . . . 1.66 −1.00 * .F 1.35 0.76 Leu 159 A A . . . . . 1.61 −1.00 . . F 1.20 1.54 Glu 160 A A. . . . . 1.50 −1.43 . . F 0.90 1.98 Glu 161 A A . . . . . 1.89 −1.41 *. F 0.90 3.16 Lys 162 A A . . . . . 1.30 −1.91 * . F 0.90 7.66 Glu 163 AA . . . . . 1.08 −1.91 . . F 0.90 3.10 Asn 164 A A . . . . . 1.03−1.23 * * F 0.90 1.48 Lys 165 A A . . . . . 1.08 −0.59 * . F 0.75 0.55Ile 166 A A . . . . . 1.08 −0.59 * * . 0.60 0.63 Leu 167 A A . . . . .0.72 −0.59 * * . 0.76 0.68 Val 168 A A . . . . . 0.38 −0.50 . * . 0.920.49 Lys 169 A A . . . . . 0.13 −0.07 * * F 0.93 0.69 Glu 170 A . . . .T . −0.61 0.00 * * F 1.64 1.32 Thr 171 . . . . T T . −0.42 0.10 . * F1.60 1.54 Gly 172 . . . . T T . −0.50 0.24 * . F 1.29 0.67 Tyr 173 . . .. T T . 0.11 0.93 * * . 0.68 0.27 Phe 174 . . B B . . . −0.28 1.69 . . .−0.28 0.29 Phe 175 . . B B . . . −0.28 1.63 . * . −0.44 0.29 Ile 176 . .B B . . . −0.82 1.60 . . . −0.60 0.32 Tyr 177 . . B B . . . −1.29 1.49 .. . −0.60 0.28 Gly 178 . . . B T . . −1.29 1.39 . . . −0.20 0.26 Gln 179. . . B T . . −0.90 1.36 . . . −0.20 0.59 Val 180 . . . B . . C −0.201.16 . . . −0.40 0.54 Leu 181 . . . B . . C 0.73 0.40 . . . −0.10 0.92Tyr 182 . . . . T T . 0.67 −0.03 . . . 1.25 1.06 Thr 183 . . . . T T .0.77 0.06 . . F 0.80 2.06 Asp 184 . . . . T T . 0.18 0.17 . . F 0.803.91 Lys 185 A . . . . T . 0.43 −0.01 . . F 1.00 2.52 Thr 186 A A . . .. . 0.90 −0.16 . . F 0.60 1.73 Tyr 187 A A . . . . . 1.11 −0.21 . . .0.45 1.03 Ala 188 A A . . . . . 0.61 0.29 . . . −0.30 0.70 Met 189 A A .. . . . −0.28 0.97 . . . −0.60 0.40 Gly 190 A A . B . . . −0.32 1.17 * .. −0.60 0.18 His 191 A A . B . . . 0.10 0.81 * . . −0.60 0.31 Leu 192 AA . B . . . 0.39 0.31 . . . −0.30 0.61 Ile 193 A A . B . . . 1.02 −0.30. . . 0.45 1.22 Gln 194 A A . B . . . 0.77 −0.73 . * . 0.75 1.80 Arg 195A A . B . . . 1.08 −0.59 * * F 0.90 1.62 Lys 196 A A . B . . . 0.26−0.77 * * F 0.90 3.14 Lys 197 A A . B . . . 0.37 −0.81 . * F 0.90 1.35Val 198 . A B B . . . 0.91 −0.43 * * . 0.30 0.60 His 199 . A B B . . .0.91 0.00 * * . 0.30 0.29 Val 200 . A B B . . . 0.80 0.00 * * . 0.300.25 Phe 201 . . B B . . . −0.06 0.00 * . . 0.30 0.57 Gly 202 A . . B .. . −0.40 0.04 . * . −0.30 0.35 Asp 203 A . . . . . . −0.36 −0.07 * . .0.50 0.63 Glu 204 A . . . . . . −1.18 −0.03 * . . 0.50 0.60 Leu 205 A .. B . . . −0.63 −0.17 . . . 0.30 0.45 Ser 206 A . . B . . . −0.74 −0.11. . . 0.30 0.39 Leu 207 A . . B . . . −1.10 0.57 . * . −0.60 0.18 Val208 A . . B . . . −0.99 1.36 . * . −0.60 0.19 Thr 209 A . . B . . .−1.66 0.67 * * . −0.60 0.28 Leu 210 A . . B . . . −1.73 0.86 * . . −0.600.18 Phe 211 A . . B . . . −1.43 0.86 * . . −0.60 0.17 Arg 212 A . . B .. . −0.62 0.61 * . . −0.60 0.21 Cys 213 . . . B T . . −0.37 0.53 * . .−0.20 0.41 Ile 214 . . . B T . . −0.27 0.46 * . . −0.20 0.46 Gln 215 . .. B T . . 0.54 0.10 * . . 0.10 0.37 Asn 216 . . . B . . C 0.93 0.10 * .. 0.05 1.19 Met 217 . . . B . . C 0.01 0.01 * . F 0.20 2.44 Pro 218 . .. B . . C 0.47 0.01 * . F 0.44 1.16 Glu 219 . . . . T . . 1.36 0.04 * .F 1.08 1.12 Thr 220 . . . . . . C 1.36 0.04 * . F 1.12 1.82 Leu 221 . .. . . . C 1.06 −0.17 * . F 1.96 1.89 Pro 222 . . . . T . . 0.99 −0.21 .. F 2.40 1.46 Asn 223 . . . . T . . 0.96 0.36 . . F 1.41 0.54 Asn 224 .. . . T T . 0.66 0.63 . . F 1.22 1.03 Ser 225 . . . . T T . 0.38 0.33 .. F 1.13 0.89 Cys 226 . . . . T T . 0.84 0.40 . . . 0.74 0.56 Tyr 227 .. . . T T . 0.17 0.43 . . . 0.20 0.35 Ser 228 A . . . . . . −0.42 0.71 .. . −0.40 0.18 Ala 229 A A . . . . . −0.38 0.83 . . . −0.60 0.34 Gly 230A A . . . . . −0.89 0.26 . . . −0.30 0.43 Ile 231 A A . . . . . −0.220.19 * . . −0.30 0.27 Ala 232 A A . . . . . 0.02 −0.20 * . . 0.30 0.46Lys 233 A A . . . . . −0.02 −0.70 . . . 0.60 0.80 Leu 234 A A . . . . .0.57 −0.70 . . F 0.90 1.13 Glu 235 A A . . . . . 0.91 −1.39 . . F 0.901.87 Glu 236 A A . . . . . 0.99 −1.89 . . F 0.90 1.62 Gly 237 A A . . .. . 1.58 −1.20 . * F 0.90 1.62 Asp 238 A A . . . . . 0.72 −1.49 . * F0.90 1.62 Glu 239 A A . . . . . 0.94 −0.80 * * F 0.75 0.77 Leu 240 A A .. . . . 0.06 −0.30 * * . 0.30 0.79 Gln 241 A A . . . . . −0.16 −0.04 * .. 0.30 0.33 Leu 242 A A . . . . . 0.30 0.39 * . . −0.30 0.30 Ala 243 A A. . . . . 0.30 0.39 * . . −0.30 0.70 Ile 244 A A . . . . . 0.30 −0.30. * . 0.30 0.70 Pro 245 A . . . . T . 0.52 −0.30 . * F 1.00 1.37 Arg 246A . . . . T . 0.52 −0.49 . * F 1.00 1.37 Glu 247 A . . . . T . 0.44−0.59 * * F 1.30 3.38 Asn 248 A . . . . T . 0.73 −0.59 * * F 1.30 1.53Ala 249 A . . . . . . 0.81 −0.63 * * . 0.95 1.05 Gln 250 A . . . . . .1.02 0.06 * * . −0.10 0.50 Ile 251 A . . . . . . 0.57 0.06 * * . 0.150.52 Ser 252 . . . . . . C 0.57 0.09 . * . 0.60 0.51 Leu 253 . . . . . .C −0.29 −0.41 . * F 1.60 0.49 Asp 254 . . . . T T . −0.01 −0.17 . * F2.25 0.52 Gly 255 . . . . T T . −0.71 −0.37 . * F 2.50 0.56 Asp 256 . .. . T T . −0.52 0.03 . * F 1.65 0.59 Val 257 A . . . . T . −0.57 0.13. * F 1.00 0.30 Thr 258 A . . B . . . −0.34 0.56 . * . −0.10 0.30 Phe259 A . . B . . . −1.16 0.63 . * . −0.35 0.18 Phe 260 A . . B . . .−0.77 1.31 . * . −0.60 0.20 Gly 261 A A . . . . . −1.58 0.67 . * . −0.600.28 Ala 262 A A . . . . . −1.53 0.87 . * . −0.60 0.27 Leu 263 A A . . .. . −1.61 0.77 * . . −0.60 0.26 Lys 264 A A . . . . . −1.30 0.41 * . .−0.60 0.33 Leu 265 A A . . . . . −0.99 0.41 . . . −0.60 0.42 Leu 266 A A. . . . . −1.03 0.34 * . . −0.30 0.65

[0085] In another embodiment, the invention provides antibodies thatbind a polypeptide comprising, or alternatively consisting of, anepitope-bearing portion of a polypeptide of the invention. The epitopeof this polypeptide portion may be an immunogenic or antigenic epitopeof a polypeptide of the invention. An “immunogenic epitope” is definedas a part of a protein that elicits an antibody response when the wholeprotein is the immunogen. On the other hand, a region of a proteinmolecule to which an antibody can bind is defined as an “antigenicepitope.” The number of immunogenic epitopes of a protein generally isless than the number of antigenic epitopes. See, for instance, Geysen etal., Proc. Natl. Acad. Sci. USA 81:3998-4002 (1983).

[0086] As to the selection of polypeptides bearing an antigenic epitope(i.e., that contain a region of a protein molecule to which an antibodycan bind), it is well known in that art that relatively short syntheticpeptides that mimic part of a protein sequence are routinely capable ofeliciting an antiserum that reacts with the partially mimicked protein.See, for instance, Sutcliffe, J. G., Shinnick, T. M., Green, N. andLearner, R. A. (1983) “Antibodies that react with predetermined sites onproteins”, Science, 219:660-666. Peptides capable of elicitingprotein-reactive sera are frequently represented in the primary sequenceof a protein, can be characterized by a set of simple chemical rules,and are confined neither to immunodominant regions of intact proteins(i.e., immunogenic epitopes) nor to the amino or carboxyl terminals.Antigenic epitope-bearing peptides and polypeptides of the invention aretherefore useful to raise antibodies, including monoclonal antibodies,that bind specifically to a polypeptide of the invention. See, forinstance, Wilson et al., Cell 37:767-778 (1984) at 777.

[0087] In specific embodiments, antibodies of the present invention bindantigenic epitope-bearing peptides and polypeptides of BLyS andpreferably contain a sequence of at least 4, at least 5, at least 6, atleast 7, more preferably at least 8, at least 9, at least 10, at least11, at least 12, at least 13, at least 14, at least 15, at least 20, atleast 25, at least 30, at least 40, at least 50, and, most preferably,between about 15 to about 30 amino acids contained within the amino acidsequence of a BLyS polypeptide. Preferred polypeptides comprisingimmunogenic or antigenic epitopes are at least 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acidresidues in length. Additional non-exclusive preferred antigenicepitopes include the antigenic epitopes disclosed herein, as well asportions thereof.

[0088] Non-limiting examples of antigenic polypeptides or peptides thatcan be used to generate BLyS-specific antibodies and which may be boundby the antibodies of the invention include: a polypeptide comprising, oralternatively consisting of, amino acid residues from about Phe-115 toabout Leu-147 in SEQ ID NO:3228; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Ile-150 toabout Tyr-163 in SEQ ID NO:3228; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Ser-171 toabout Phe-194 in SEQ ID NO:3228; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Glu-223 toabout Tyr-246 in SEQ ID NO:3228; and a polypeptide comprising, oralternatively consisting of, amino acid residues from about Ser-271 toabout Phe-278 in FIGS. 1A and 1B (SEQ ID NO:3228). In this context,“about” means the particularly recited ranges and ranges larger orsmaller by several, a few, 5, 4, 3, 2 or 1 amino acid residues at eitheror both the amino- and carboxy-termini. These polypeptide fragments havebeen determined to bear antigenic epitopes of the BLyS polypeptide bythe analysis of the Jameson-Wolf antigenic index, as disclosed Table 9,above.

[0089] Non-limiting examples of antigenic polypeptides or peptides thatcan be used to generate BLyS-specific antibodies and which may be boundby the antibodies of the invention include: a polypeptide comprising, oralternatively consisting of, amino acid residues from about Pro-32 toabout Leu-47 in SEQ ID NO:3229; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Glu-116 toabout Ser-143 in SEQ ID NO:3229; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Phe-153 toabout Tyr-173 in SEQ ID NO:3229; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Pro-218 toabout Tyr-227 in SEQ ID NO:3229; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Ala-232 toabout Gln-241 in SEQ ID NO:3229; a polypeptide comprising, oralternatively consisting of, amino acid residues from about Ile-244 toabout Ala-249 in SEQ ID NO:3229; and a polypeptide comprising, oralternatively consisting of, amino acid residues from about Ser-252 toabout Val-257 in SEQ ID NO:3229. In this context, “about” means theparticularly recited ranges and ranges larger or smaller by several, afew, 5, 4, 3, 2 or 1 amino acid residues at either or both the amino-and carboxy-termini. These polypeptide fragments have been determined tobear antigenic epitopes of the BLyS polypeptide by the analysis of theJameson-Wolf antigenic index, as disclosed in Table 10 generated by theProtean component of the DNA*STAR computer program (as set forth above).

[0090] BLyS epitope-bearing peptides and polypeptides may be produced byany conventional means. See, e.g., Houghten, R. A. (1985) General methodfor the rapid solid-phase synthesis of large numbers of peptides:specificity of antigen-antibody interaction at the level of individualamino acids. Proc. Natl. Acad. Sci. USA 82:5131-5135; this “SimultaneousMultiple Peptide Synthesis (SMPS)” process is further described in U.S.Pat. No. 4,631,211 to Houghten et al. (1986).

[0091] The present invention encompasses antibodies that bindpolypeptides comprising, or alternatively consisting of, an epitope ofthe polypeptide having an amino acid sequence of SEQ ID NO:3228, or anepitope of the polypeptide sequence encoded by a polynucleotide sequencecontained in ATCC deposit No. 97768, or encoded by a polynucleotide thathybridizes to cDNA sequence contained in ATCC deposit No. 97768 (e.g.,under hybridization conditions described herein).

[0092] The present invention also encompasses antibodies that bindpolypeptides comprising, or alternatively consisting of, an epitope ofthe polypeptide having an amino acid sequence of SEQ ID NO:3229, or anepitope of the polypeptide sequence encoded by a polynucleotide sequencecontained in ATCC deposit No. 203518, or encoded by a polynucleotidethat hybridizes to the cDNA sequence contained in ATCC deposit No.203518 (e.g., under hybridization conditions described herein).

[0093] The term “epitopes,” as used herein, refers to portions of apolypeptide having antigenic or immunogenic activity in an animal,preferably a mammal, and most preferably in a human. In a preferredembodiment, the present invention encompasses antibodies that bind apolypeptide comprising an epitope. An “immunogenic epitope,” as usedherein, is defined as a portion of a protein that elicits an antibodyresponse in an animal, as determined by any method known in the art, forexample, by the methods for generating antibodies described infra. (See,for example, Geysen et al., Proc. Natl. Acad. Sci. USA 81:3998-4002(1983)). The term “antigenic epitope,” as used herein, is defined as aportion of a protein to which an antibody can immunospecifically bindits antigen as determined by any method well known in the art, forexample, by the immunoassays described herein. Immunospecific bindingexcludes non-specific binding but does not necessarily excludecross-reactivity with other antigens. Antigenic epitopes need notnecessarily be immunogenic.

[0094] BLyS polypeptide fragments which function as epitopes may beproduced by any conventional means. (See, e.g., Houghten, Proc. Natl.Acad. Sci. USA 82:5131-5135 (1985), further described in U.S. Pat. No.4,631,211).

[0095] In the present invention, antibodies of the present inventionbind antigenic epitopes preferably containing a sequence of at least 4,at least 5, at least 6, at least 7, more preferably at least 8, at least9, at least 10, at least 11, at least 12, at least 13, at least 14, atleast 15, at least 20, at least 25, at least 30, at least 40, at least50, and, most preferably, between about 15 to about 30 amino acids.Preferred polypeptides comprising immunogenic or antigenic epitopes thatmay be bound by antibodies of the present invention are at least 10, 15,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100amino acid residues in length. Additional non-exclusive preferredantigenic epitopes include the antigenic epitopes disclosed herein, aswell as portions thereof. Antigenic epitopes are useful, for example, toraise antibodies, including monoclonal antibodies, that specificallybind the epitope. Preferred antigenic epitopes include the antigenicepitopes disclosed herein, as well as any combination of two, three,four, five or more of these antigenic epitopes. Antigenic epitopes canbe used as the target molecules in immunoassays. (See, for instance,Wilson et al., Cell 37:767-778 (1984); Sutcliffe et al., Science219:660-666 (1983)).

[0096] Similarly, immunogenic epitopes can be used, for example, toinduce antibodies according to methods well known in the art. (See, forinstance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al.,Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle et al., J. Gen. Virol.66:2347-2354 (1985). Preferred immunogenic epitopes include theimmunogenic epitopes disclosed herein, as well as any combination oftwo, three, four, five or more of these immunogenic epitopes. Thepolypeptides comprising one or more immunogenic epitopes of BLyS may bepresented for eliciting an antibody response together with a carrierprotein, such as an albumin, to an animal system (such as rabbit ormouse), or, if the polypeptide is of sufficient length (at least about25 amino acids), the polypeptide may be presented without a carrier.However, immunogenic epitopes comprising as few as 8 to 10 amino acidshave been shown to be sufficient to raise antibodies capable of bindingto, at the very least, linear epitopes in a denatured polypeptide (e.g.,in Western blotting).

[0097] Epitope-bearing BLyS polypeptides may be used to induceantibodies according to methods well known in the art including, but notlimited to, in vivo immunization, in vitro immunization, and phagedisplay methods. See, e.g., Sutcliffe et al., supra; Wilson et al.,supra, and Bittle et al., J. Gen. Virol., 66:2347-2354 (1985). If invivo immunization is used, animals may be immunized with free peptide;however, anti-peptide antibody titer may be boosted by coupling thepeptide to a macromolecular carrier, such as keyhole limpet hemocyanin(KLH) or tetanus toxoid. For instance, peptides containing cysteineresidues may be coupled to a carrier using a linker such asmaleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptidesmay be coupled to carriers using a more general linking agent such asglutaraldehyde. Animals such as rabbits, rats and mice are immunizedwith either free or carrier-coupled peptides, for instance, byintraperitoneal and/or intradermal injection of emulsions containingabout 100 micrograms of peptide or carrier protein and Freund's adjuvantor any other adjuvant known for stimulating an immune response. Severalbooster injections may be needed, for instance, at intervals of abouttwo weeks, to provide a useful titer of anti-peptide antibody which canbe detected, for example, by ELISA assay using free peptide adsorbed toa solid surface. The titer of anti-peptide antibodies in serum from animmunized animal may be increased by selection of anti-peptideantibodies, for instance, by adsorption to the peptide on a solidsupport and elution of the selected antibodies according to methods wellknown in the art.

[0098] As one of skill in the art will appreciate, and as discussedabove, the antibodies of the present invention may bind polypeptidescomprising an immunogenic or antigenic epitope fused to otherpolypeptide sequences. For example, the BLyS polypeptides may be fusedwith the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), orportions thereof (CH1, CH2, CH3, or any combination thereof and portionsthereof), or albumin (including but not limited to recombinant humanalbumin or fragments or variants thereof (see, e.g., U.S. Pat. No.5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No.5,766,883, issued Jun. 16, 1998, herein incorporated by reference intheir entirety)), resulting in chimeric polypeptides. Such fusionproteins may facilitate purification and may increase half-life in vivo.This has been shown for chimeric proteins consisting of the first twodomains of the human CD4-polypeptide and various domains of the constantregions of the heavy or light chains of mammalian immunoglobulins. See,e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanceddelivery of an antigen across the epithelial barrier to the immunesystem has been demonstrated for antigens (e.g., insulin) conjugated toan FcRn binding partner such as IgG or Fc fragments (see, e.g., PCTPublications WO 96/22024 and WO 99/04813). IgG Fusion proteins that havea disulfide-linked dimeric structure due to the IgG portion disulfidebonds have also been found to be more efficient in binding andneutralizing other molecules than monomeric polypeptides or fragmentsthereof alone. See, e.g., Fountoulakis et al., J. Biochem.,270:3958-3964 (1995). Nucleic acids encoding the above epitopes can alsobe recombined with a gene of interest as an epitope tag (e.g., thehemagglutinin (“HA”) tag or flag tag) to aid in detection andpurification of the expressed polypeptide. For example, a systemdescribed by Janknecht et al. allows for the ready purification ofnon-denatured fusion proteins expressed in human cell lines (Janknechtet al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-897). In this system,the gene of interest is subcloned into a vaccinia recombination plasmidsuch that the open reading frame of the gene is translationally fused toan amino-terminal tag consisting of six histidine residues. The tagserves as a matrix-binding domain for the fusion protein. Extracts fromcells infected with the recombinant vaccinia virus are loaded onto Ni²⁺nitriloacetic acid-agarose column and histidine-tagged proteins can beselectively eluted with imidazole-containing buffers.

[0099] In another embodiment, the antibodies of the present inventionbind BLyS polypeptides and/or the epitope-bearing fragments thereof thatare fused with a heterologous antigen (e.g., polypeptide, carbohydrate,phospholipid, or nucleic acid). In specific embodiments, theheterologous antigen is an immunogen.

[0100] In a more specific embodiment, the heterologous antigen is thegp120 protein of HIV, or a fragment thereof.

[0101] In another embodiment, antibodies of the present invention bindBLyS polypeptides and/or the epitope-bearing fragments thereof that arefused with polypeptide sequences of another TNF ligand family member (orbiologically active fragments or variants thereof). In a specificembodiment, the antibodies of the present invention bind BLySpolypeptides of the present invention are fused with a CD40L polypeptidesequence. In a preferred embodiment, the CD40L polypeptide sequence issoluble.

[0102] In another embodiment, antibodies of the present invention bindmutant BLyS polypeptides that have been generated by random mutagenesisof a polynucleotide encoding the BLyS polypeptide, by error-prone PCR,random nucleotide insertion or other methods prior to recombination. Inanother embodiment, antibodies of the present invention bind one or morecomponents, motifs, sections, parts, domains, fragments, etc., of BLySrecombined with one or more components, motifs, sections, parts,domains, fragments, etc. of one or more heterologous molecules. Inpreferred embodiments, the heterologous molecules are, for example,TNF-alpha, lymphotoxin-alpha (LT-alpha, also known as TNF-beta), LT-beta(found in complex heterotrimer LT-alpha2-beta), OPGL, FasL, CD27L,CD30L, CD40L, 4-1BBL, DcR3, OX40L, TNF-gamma (International PublicationNo. WO 96/14328), AIM-I (International Publication No. WO 97/33899),AIM-II (International Publication No. WO 97/34911), APRIL (J. Exp. Med.188(6):1185-1190), endokine-alpha (International Publication No. WO98/07880), OPG, OX40, and nerve growth factor (NGF), and soluble formsof Fas, CD30, CD27, CD40 and 4-IBB, TR2 (International Publication No.WO 96/34095), DR3 (International Publication No. WO 97/33904), DR4(International Publication No. WO 98/32856), TR5 (InternationalPublication No. WO 98/30693), TR6 (International Publication No. WO98/30694), TR7 (International Publication No. WO 98/41629), TRANK, TR9(International Publication No. WO 98/56892), TR10 (InternationalPublication No. WO 98/54202),312C2 (International Publication No. WO98/06842), TR12, CAD, and v-FLIP. In further embodiments, theheterologous molecules are any member of the TNF family.

[0103] In another preferred embodiment, antibodies of the presentinvention bind BLyS polypeptides of the invention (includingbiologically active fragments or variants thereof), that are fused withsoluble APRIL polypeptides (e.g., amino acid residues 105 through 250 ofSEQ ID NO:3239), or biologically active fragments or variants thereof.

[0104] To improve or alter the characteristics of BLyS polypeptides,protein engineering may be employed. Recombinant DNA technology known tothose skilled in the art can be used to create novel mutant proteins or“muteins including single or multiple amino acid substitutions,deletions, additions or fusion proteins. Such modified polypeptides canshow, e.g., enhanced activity or increased stability. In addition, theymay be purified in higher yields and show better solubility than thecorresponding natural polypeptide, at least under certain purificationand storage conditions. For instance, for many proteins, including theextracellular domain or the mature form(s) of a secreted protein, it isknown in the art that one or more amino acids may be deleted from theN-terminus or C-terminus without substantial loss of biologicalfunction. For instance, Ron et al., J. Biol. Chem., 268:2984-2988 (1993)reported modified KGF proteins that had heparin binding activity even if3, 8, or 27 amino-terminal amino acid residues were missing.Accordingly, antibodies of the present invention may bind BLySpolypeptide mutants or variants generated by protein engineering.

[0105] In the present case, since the protein of the invention is amember of the TNF polypeptide family, deletions of N-terminal aminoacids up to the Gly (G) residue at position 191 in SEQ ID NO:3228 mayretain some biological activity such as, for example, the ability tostimulate lymphocyte (e.g., B cell) proliferation, differentiation,and/or activation, and cytotoxicity to appropriate target cells.Polypeptides having further N-terminal deletions including the Gly (G)residue would not be expected to retain biological activities because itis known that this residue in TNF-related polypeptides is in thebeginning of the conserved domain required for biological activities.However, even if deletion of one or more amino acids from the N-terminusof a protein results in modification or loss of one or more biologicalfunctions of the protein, other functional activities may still beretained. Thus, the ability of the shortened protein to induce and/orbind to antibodies which recognize the complete or extracellular domainof the protein generally will be retained when less than the majority ofthe residues of the complete or extracellular domain of the protein areremoved from the N-terminus. Whether a particular polypeptide lackingN-terminal residues of a complete protein retains such immunologicactivities can readily be determined by routine methods described hereinand otherwise known in the art.

[0106] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues deleted from theamino terminus of the amino acid sequence of the BLyS of SEQ ID NO:3228,up to the glycine residue at position 191 (Gly-191 residue from theamino terminus). In particular, the present invention providesantibodies that bind polypeptides comprising, or alternativelyconsisting of, the amino acid sequence of residues n¹-285 of SEQ IDNO:3228, where n¹ is an integer in the range of the amino acid positionof amino acid residues 2-190 of the amino acid sequence in SEQ IDNO:3228. More in particular, the invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, an amino acidsequence selected from the group consisting of residues 2-285, 3-285,4-285, 5-285, 6-285, 7-285, 8-285, 9-285, 10-285, 11-285, 12-285,13-285, 14-285, 15-285, 16-285, 17-285, 18-285, 19-285, 20-285, 21-285,22-285, 23-285, 24-285, 25-285, 26-285, 27-285, 28-285, 29-285, 30-285,31-285, 32-285, 33-285, 34-285, 35-285, 36-285, 37-285, 38-285, 39-285,40-285, 41-285, 42-285, 43-285, 44-285, 45-285, 46-285, 47-285, 48-285,49-285, 50-285, 51-285, 52-285, 53-285, 54-285, 55-285, 56-285, 57-285,58-285, 59-285, 60-285, 61-285, 62-285, 63-285, 64-285, 65-285, 66-285,67-285, 68-285, 69-285, 70-285, 71-285, 72-285, 73-285, 74-285, 75-285,76-285, 77-285, 78-285, 79-285, 80-285, 81-285, 82-285, 83-285, 84-285,85-285, 86-285, 87-285, 88-285, 89-285, 90-285, 91-285, 92-285, 93-285,94-285, 95-285, 96-285, 97-285, 98-285, 99-285, 100-285, 101-285,102-285, 103-285, 104-285, 105-285, 106-285, 107-285, 108-285, 109-285,110-285, 111-285, 112-285, 113-285, 114-285, 115-285, 116-285, 117-285,118-285, 119-285, 120-285, 121-285, 122-285, 123-285, 124-285, 125-285,126-285, 127-285, 128-285, 129-285, 130-285, 131-285, 132-285, 133-285,134-285, 135-285, 136-285, 137-285, 138-285, 139-285, 140-285, 141-285,142-285, 143-285, 144-285, 145-285, 146-285, 147-285, 148-285, 149-285,150-285, 151-285, 152-285, 153-285, 154-285, 155-285, 156-285, 157-285,158-285, 159-285, 160-285, 161-285, 162-285, 163-285, 164-285, 165-285,166-285, 167-285, 168-285, 169-285, 170-285, 171-285, 172-285, 173-285,174-285, 175-285, 176-285, 177-285, 178-285, 179-285, 180-285, 181-285,182-285, 183-285, 184-285, 185-285, 186-285, 187-285, 188-285, 189-285,and 190-285 of SEQ ID NO:3228. The present invention is also directed toantibodies that bind BLyS polypeptides comprising, or alternatively,consisting of, a contiguous sequence of amino acid residues at least80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the aminoacid sequence of BLyS polypeptides described above.

[0107] Furthermore, since the predicted extracellular domain of the BLySpolypeptides of the invention may itself elicit biological activity,deletions of N- and C-terminal amino acid residues from the predictedextracellular region of the polypeptide (spanning positions Gln-73 toLeu-285 of SEQ ID NO:3228) may retain some biological activity such as,for example, ligand binding, stimulation of lymphocyte (e.g., B cell)proliferation, differentiation, and/or activation, and modulation ofcell replication or modulation of target cell activities. However, evenif deletion of one or more amino acids from the N-terminus of thepredicted extracellular domain of a BLyS polypeptide results inmodification or loss of one or more biological functions of thepolypeptide, other functional activities may still be retained. Thus,the ability of the shortened polypeptides to induce and/or bind toantibodies which recognize the complete or mature or extracellulardomains of the polypeptides generally will be retained when less thanthe majority of the residues of the complete or mature or extracellulardomains of the polypeptides are removed from the N-terminus. Whether aparticular polypeptide lacking N-terminal residues of a completepolypeptide retains such immunologic activities can readily bedetermined by routine methods described herein and otherwise known inthe art.

[0108] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues deleted from theamino terminus of the amino acid sequence of BLyS shown in SEQ IDNO:3228, up to the glycine residue at position number 280. Inparticular, the present invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, the amino acidsequence of residues n²-285 of SEQ ID NO:3228, where n² is an integer inthe range of the amino acid position of amino acid residues 73-280 inSEQ ID NO:3228, and 73 is the position of the first residue from theN-tenninus of the predicted extracellular domain of the BLyS polypeptide(disclosed in SEQ ID NO:3228). More in particular, in certainembodiments, the invention provides antibodies that bind polypeptidescomprising, or alternatively consisting of, an amino acid sequenceselected from the group consisting of residues of Q-73 to L-285; G-74 toL-285; D-75 to L-285; L-76 to L-285; A-77 to L-285; S-78 to L-285; L-79to L-285; R-80 to L-285; A-81 to L-285; E-82 to L-285; L-83 to L-285;Q-84 to L-285; G-85 to L-285; H-86 to L-285; H-87 to L-285; A-88 toL-285; E-89 to L-285; K-90 to L-285; L-91 to L-285; P-92 to L-285; A-93to L-285; G-94 to L-285; A-95 to L-285; G-96 to L-285; A-97 to L-285;P-98 to L-285; K-99 to L-285; A-100 to L-285; G-101 to L-285; L-102 toL-285; E-103 to L-285; E-104 to L-285; A-105 to L-285; P-106 to L-285;A-107 to L-285; V-108 to L-285; T-109 to L-285; A-110 to L-285; G-111 toL-285; L-112 to L-285; K-113 to L-285; I-114 to L-285; F-115 to L-285;E-116 to L-285; P-117 to L-285; P-118 to L-285; A-119 to L-285; P-120 toL-285; G-121 to L-285; E-122 to L-285; G-123 to L-285; N-124 to L-285;S-125 to L-285; S-126 to L-285; Q-127 to L-285; N-128 to L-285; S-129 toL-285; R-130 to L-285; N-131 to L-285; K-132 to L-285; R-133 to L-285;A-134 to L-285; V-135 to L-285; Q-136 to L-285; G-137 to L-285; P-138 toL-285; E-139 to L-285; E-140 to L-285; T-141 to L-285; V-142 to L-285;T-143 to L-285; Q-144 to L-285; D-145 to L-285; C-146 to L-285; L-147 toL-285; Q-148 to L-285; L-149 to L-285; I-150 to L-285; A-151 to L-285;D-152 to L-285; S-153 to L-285; E-154 to L-285; T-155 to L-285; P-156 toL-285; T-157 to L-285; I-158 to L-285; Q-159 to L-285; K-160 to L-285;G-161 to L-285; S-162 to L-285; Y-163 to L-285; T-164 to L-285; F-165 toL-285; V-166 to L-285; P-167 to L-285; W-168 to L-285; L-169 to L-285;L-170 to L-285; S-171 to L-285; F-172 to L-285; K-173 to L-285; R-174 toL-285; G-175 to L-285; S-176 to L-285; A-177 to L-285; L-178 to L-285;E-179 to L-285; E-180 to L-285; K-181 to L-285; E-182 to L-285; N-183 toL-285; K-184 to L-285; I-185 to L-285; L-186 to L-285; V-187 to L-285;K-188 to L-285; E-189 to L-285; T-190 to L-285; G-191 to L-285; Y-192 toL-285; F-193 to L-285; F-194 to L-285; I-195 to L-285; Y-196 to L-285;G-197 to L-285; Q-198 to L-285; V-199 to L-285; L-200 to L-285; Y-201 toL-285; T-202 to L-285; D-203 to L-285; K-204 to L-285; T-205 to L-285;Y-206 to L-285; A-207 to L-285; M-208 to L-285; G-209 to L-285; H-210 toL-285; L-211 to L-285; I-212 to L-285; Q-213 to L-285; R-214 to L-285;K-215 to L-285; K-216 to L-285; V-217 to L-285; H-218 to L-285; V-219 toL-285; F-220 to L-285; G-221 to L-285; D-222 to L-285; E-223 to L-285;L-224 to L-285; S-225 to L-285; L-226 to L-285; V-227 to L-285; T-228 toL-285; L-229 to L-285; F-230 to L-285; R-231 to L-285; C-232 to L-285;I-233 to L-285; Q-234 to L-285; N-235 to L-285; M-236 to L-285; P-237 toL-285; E-238 to L-285; T-239 to L-285; L-240 to L-285; P-241 to L-285;N-242 to L-285; N-243 to L-285; S-244 to L-285; C-245 to L-285; Y-246 toL-285; S-247 to L-285; A-248 to L-285; G-249 to L-285; I-250 to L-285;A-251 to L-285; K-252 to L-285; L-253 to L-285; E-254 to L-285; E-255 toL-285; G-256 to L-285; D-257 to L-285; E-258 to L-285; L-259 to L-285; Q-260 to L-285; L-261 to L-285; A -262 to L-285; I-263 to L-285; P -264to L-285; R-265 to L-285; E-266 to L-285; N-267 to L-285; A-268 toL-285; Q-269 to L-285; I-270 to L-285; S-271 to L-285; L-272 to L-285;D-273 to L-285; G-274 to L-285; D-275 to L-285; V-276 to L-285; T-277 toL-285; F-278 to L-285; F-279 to L-285; and G-280 to L-285 of SEQ IDNO:3228 The present invention is also directed to antibodies that bindBLyS polypeptides comprising, or alternatively, consisting of; acontiguous sequence of amino acid residues at least 80%, 85%, 90%, 92%,95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of BLySpolypeptides described above.

[0109] Highly preferred embodiments of the invention are directed toantibodies that bind polypeptides comprising, or alternativelyconsisting of, a polypeptide having an amino acid sequence least 80%,85%, 90% identical and more preferably at least 95%, 96%, 97%, 98%, 99%or 100% identical to BLyS polypeptide having the amino acid sequence atpositions 134-285 of SEQ ID NO:3228.

[0110] Preferred embodiments of the invention are directed to antibodiesthat bind polypeptides comprising, or alternatively consisting of, apolypeptide having an amino acid sequence at least 90% identical to aBLyS polypeptide having the amino acid sequence at positions 134-285 ofSEQ ID NO:3228. More preferred embodiments of the invention are directedto antibodies that bind polypeptides comprising, or alternativelyconsisting of, a polypeptide having an amino acid sequence at least 95%identical to a BLyS polypeptide having the amino acid sequence atpositions 134-285 of SEQ ID NO:3228. More preferred embodiments of theinvention are directed to antibodies that bind polypeptides comprising,or alternatively consisting of, a polypeptide having an amino acidsequence at least 96% identical to a BLyS polypeptide having the aminoacid sequence at positions 134-285 of SEQ ID NO:3228.

[0111] Additionally, more preferred embodiments of the invention aredirected to antibodies that bind polypeptides comprising, oralternatively consisting of, a polypeptide having an amino acid sequenceat least 97% to a BLyS polypeptide having the amino acid sequence atpositions 134-285 of SEQ ID NO:3228. Additionally, more preferredembodiments of the invention are directed to antibodies that bindpolypeptides comprising, or alternatively consisting of, a polypeptidehaving an amino acid sequence at least 98% to a BLyS polypeptide havingthe amino acid sequence at positions 134-285 of SEQ ID NO:3228.Additionally, more preferred embodiments of the invention are directedto antibodies that bind polypeptides comprising, or alternativelyconsisting of, a polypeptide having an amino acid sequence at least 99%identical to BLyS polypeptide having the amino acid sequence atpositions 134-285 of SEQ ID NO:3228.

[0112] In specific embodiments, antibodies of the present invention bindpolypeptides comprising, or alternatively consisting of, one of thefollowing N-terminally deleted polypeptide fragments of BLyS: amino acidresidues Ala-71 through Leu-285, amino acid residues Ala-81 throughLeu-285, amino acid residues Leu-112 through Leu-285, amino acidresidues Ala-134 through Leu-285, amino acid residues Leu-147 throughLeu-285, and amino acid residues Gly-161 through Leu-285 of SEQ IDNO:3228.

[0113] Similarly, many examples of biologically functional C-terminaldeletion polypeptides are known. For instance, Interferon gamma shows upto ten times higher activities by deleting 8-10 amino acid residues fromthe carboxy terminus of the protein (Döbeli et al., J. Biotechnology7:199-216 (1988). Since the present protein is a member of the TNFpolypeptide family, deletions of C-terminal amino acids up to theleucine residue at position 284 are expected to retain most if not allbiological activity such as, for example, ligand binding, the ability tostimulate lymphocyte (e.g., B cell) proliferation, differentiation,and/or activation, and modulation of cell replication. Polypeptideshaving deletions of up to about 10 additional C-terminal residues (i.e.,up to the glycine residue at position 274) also may retain some activitysuch as receptor binding, although such polypeptides would lack aportion of the conserved TNF domain which extends to about Leu-284 ofSEQ ID NO:3228. However, even if deletion of one or more amino acidsfrom the C-terminus of a protein results in modification or loss of oneor more biological functions of the protein, other functional activitiesmay still be retained. Thus, the ability of the shortened protein toinduce and/or bind to antibodies which recognize the complete or matureprotein generally will be retained when less than the majority of theresidues of the complete or mature protein are removed from theC-terminus. Whether a particular polypeptide lacking C-terminal residuesof a complete protein retains such immunologic activities can readily bedetermined by routine methods described herein and otherwise known inthe art.

[0114] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues deleted from thecarboxy terminus of the amino acid sequence of the BLyS polypeptide ofSEQ ID NO:3228, up to the glycine residue at position 274 (Gly-274). Inparticular, the present invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, the amino acidsequence of residues 1-m¹ of the amino acid sequence in SEQ ID NO:3228,where m¹ is any integer in the range of the amino acid position of aminoacid residues 274-284 in SEQ ID NO:3228. More in particular, theinvention provides antibodies that bind BLyS polypeptides comprising, oralternatively consisting of, an amino acid sequence selected from thegroup consisting of residues 1-274, 1-275, 1-276, 1-277, 1-278, 1-279,1-280, 1-281, 1-282, 1-283 and 1-284 of SEQ ID NO:3228. The presentinvention is also directed to antibodies that bind BLyS polypeptidescomprising, or alternatively, consisting of, a contiguous sequence ofamino acid residues at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or99% identical to the amino acid sequence of BLyS polypeptides describedabove.

[0115] Also provided are antibodies that bind BLyS polypeptidescomprising, or alternatively consisting of, BLyS polypeptides with oneor more amino acids deleted from both the amino and the carboxyltermini, which may be described generally as having residues n¹-m¹ ofSEQ ID NO:3228, where n¹ and m¹ are integers as defined above. Alsoincluded are antibodies that bind a polypeptide comprising, oralternatively consisting of, a portion of the complete BLyS amino acidsequence encoded by the deposited cDNA clone contained in ATCC AccessionNo. 97768 where this portion excludes from 1 to 190 amino acids from theamino terminus or from 1 to 11 amino acids from the C-terminus of thecomplete amino acid sequence (or any combination of these N-terminal andC-terminal deletions) encoded by the cDNA clone in the depositedplasmid.

[0116] Similarly, deletions of C-terminal amino acid residues of thepredicted extracellular domain of BLyS up to the leucine residue atposition 79 of SEQ ID NO:3228 may retain some biological activity, suchas, for example, ligand binding, stimulation of lymphocyte (e.g., Bcell) proliferation, differentiation, and/or activation, and modulationof cell replication or modulation of target cell activities.Polypeptides having further C-terminal deletions including Leu-79 of SEQID NO:3228 would not be expected to retain biological activities.

[0117] However, even if deletion of one or more amino acids from theC-terminus of a polypeptide results in modification or loss of one ormore biological functions of the polypeptide, other functionalactivities may still be retained. Thus, the ability of the shortenedpolypeptide to induce and/or bind to antibodies which recognize thecomplete, mature or extracellular forms of the polypeptide generallywill be retained when less than the majority of the residues of thecomplete, mature or extracellular forms of the polypeptide are removedfrom the C-terminus. Whether a particular polypeptide lacking C-terminalresidues of the predicted extracellular domain retains such immunologicactivities can readily be determined by routine methods described hereinand otherwise known in the art.

[0118] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues deleted from thecarboxy terminus of the amino acid sequence of the predictedextracellular domain of BLyS polypeptide shown in SEQ ID NO:3228, up tothe leucine residue at position 79 of SEQ ID NO:3228. In particular, thepresent invention provides antibodies that bind polypeptides comprising,or alternatively consisting of, the amino acid sequence of residues73-m² of the amino acid sequence in SEQ ID NO:3228, where m² is anyinteger in the range of the amino acid position of amino acid residues79 to 285 in the amino acid sequence in SEQ ID NO:3228, and residue 78is the position of the first residue at the C- terminus of the predictedextracellular domain of the BLyS polypeptide (disclosed in SEQ IDNO:3228). More in particular, in certain embodiments, the inventionprovides antibodies that bind polypeptides comprising, or alternativelyconsisting of, an amino acid sequence selected from the group consistingof residues Q-73 to Leu-285; Q-73 to L-284; Q-73 to K-283; Q-73 toL-282; Q-73 to A-281; Q-73 to G-280; Q-73 to F-279; Q-73 to F-278; Q-73to T-277; Q-73 to V-276; Q-73 to D-275; Q-73 to G-274; Q-73 to D-273;Q-73 to L-272; Q-73 to S-271; Q-73 to I-270; Q-73 to Q-269; Q-73 toA-268; Q-73 to N-267; Q-73 to E-266; Q-73 to R-265; Q-73 to P-264; Q-73to I-263; Q-73 to A-262; Q-73 to L-261; Q-73 to Q-260; Q-73 to L-259;Q-73 to E-258; Q-73 to D-257; Q-73 to G-256; Q-73 to E-255; Q-73 toE-254; Q-73 to L-253; Q-73 to K-252; Q-73 to A-251; Q-73 to I-250; Q-73to G-249; Q-73 to A-248; Q-73 to S-247; Q-73 to Y-246; Q-73 to C-245;Q-73 to S-244; Q-73 to N-243; Q-73 to N-242; Q-73 to P-241; Q-73 toL-240; Q-73 to T-239; Q-73 to E-238; Q-73 to P-237; Q-73 to M-236; Q-73to N-235; Q-73 to Q-234; Q-73 to I-233; Q-73 to C-232; Q-73 to R-231;Q-73 to F-230; Q-73 to L-229; Q-73 to T-228; Q-73 to V-227; Q-73 toL-226; Q-73 to S-225; Q-73 to L-224; Q-73 to E-223; Q-73 to D-222; Q-73to G-221; Q-73 to F-220; Q-73 to V-219; Q-73 to H-218; Q-73 to V-217;Q-73 to K-216; Q-73 to K-215; Q-73 to R-214; Q-73 to Q-213; Q-73 toI-212; Q-73 to L-211; Q-73 to H-210; Q-73 to G-209; Q-73 to M-208; Q-73to A-207; Q-73 to Y-206; Q-73 to T-205; Q-73 to K-204; Q-73 to D-203;Q-73 to T-202; Q-73 to Y-201; Q-73 to L-200; Q-73 to V-199; Q-73 toQ-198; Q-73 to G-197; Q-73 to Y-196; Q-73 to I-195; Q-73 to F-194; Q-73to F-193; Q-73 to Y-192; Q-73 to G-191; Q-73 to T-190; Q-73 to E-189;Q-73 to K-188; Q-73 to V-187; Q-73 to L-186; Q-73 to I-185; Q-73 toK-184; Q-73 to N-183; Q-73 to E-182; Q-73 to K-181; Q-73 to E-180; Q-73to E-179; Q-73 to L-178; Q-73 to A-177; Q-73 to S-176; Q-73 to G-175;Q-73 to R-174; Q-73 to K-173; Q-73 to F-172; Q-73 to S-171; Q-73 toL-170; Q-73 to L-169; Q-73 to W-168; Q-73 to P-167; Q-73 to V-166; Q-73to F-165; Q-73 to T-164; Q-73 to Y-163; Q-73 to S-162; Q-73 to G-161;Q-73 to K-160; Q-73 to Q-159; Q-73 to I-158; Q-73 to T-157; Q-73 toP-156; Q-73 to T-155; Q-73 to E-154; Q-73 to S-153; Q-73 to D-152; Q-73to A-151; Q-73 to I-150; Q-73 to L-149; Q-73 to Q-148; Q-73 to L-147;Q-73 to C-146; Q-73 to D-145; Q-73 to Q-144; Q-73 to T-143; Q-73 toV-142; Q-73 to T-141; Q-73 to E-140; Q-73 to E-139; Q-73 to P-138; Q-73to G-137; Q-73 to Q-136; Q-73 to V-135; Q-73 to A-134; Q-73 to R-133;Q-73 to K-132; Q-73 to N-131; Q-73 to R-130; Q-73 to S-129; Q-73 toN-128; Q-73 to Q-127; Q-73 to S-126; Q-73 to S-125; Q-73 to N-124; Q-73to G-123; Q-73 to E-122; Q-73 to G-121; Q-73 to P-120; Q-73 to A-119;Q-73 to P-118; Q-73 to P-117; Q-73 to E-116; Q-73 to F-115; Q-73 toI-114; Q-73 to K-113; Q-73 to L-112; Q-73 to G-111; Q-73 to A-110; Q-73to T-109; Q-73 to V-108; Q-73 to A-107; Q-73 to P-106; Q-73 to A-105;Q-73 to E-104; Q-73 to E-103; Q-73 to L-102; Q-73 to G-101; Q-73 toA-100; Q-73 to K-99; Q-73 to P-98; Q-73 to A-97; Q-73 to G-96; Q-73 toA-95; Q-73 to G-94; Q-73 to A-93; Q-73 to P-92; Q-73 to L-91; Q-73 toK-90; Q-73 to E-89; Q-73 to A-88; Q-73 to H-87; Q-73 to H-86; Q-73 toG-85; Q-73 to Q-84; Q-73 to L-83; Q-73 to E-82; Q-73 to A-81; Q-73 toR-80; and Q-73 to L-79 of SEQ ID NO:3228. The present invention is alsodirected to antibodies that bind BLyS polypeptides comprising, oralternatively, consisting of, a contiguous sequence of amino acidresidues at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99%identical to the amino acid sequence of BLyS polypeptides describedabove.

[0119] The invention also provides antibodies that bind polypeptideshaving one or more amino acids deleted from both the amino and thecarboxyl termini of the predicted extracellular domain of BLyS, whichmay be described generally as having residues n²-m² of SEQ ID NO:3228where n² and m² are integers as defined above.

[0120] In another embodiment, antibodies of the present invention bindpolypeptides consisting of a portion of the extracellular domain of theBLyS amino acid sequence encoded by the cDNA plasmid contained in thedeposit having ATCC accession no. 97768, where this portion excludesfrom 1 to about 206 amino acids from the amino terminus of theextracellular domain of the amino acid sequence encoded by the cDNAplasmid contained in the deposit having ATCC accession no. 97768, orfrom 1 to about 206 amino acids from the carboxy terminus of theextracellular domain of the amino acid sequence encoded by the cDNAplasmid contained in the deposit having ATCC accession no. 97768, or anycombination of the above amino terminal and carboxy terminal deletions,of the entire extracellular domain of the amino acid sequence encoded bythe cDNA plasmid contained in the deposit having ATCC accession no.97768.

[0121] As mentioned above, even if deletion of one or more amino acidsfrom the N-terminus of a polypeptide results in modification or loss ofone or more functional activities (e.g., biological activity) of thepolypeptide, other functions or biological activities may still beretained. Thus, the ability of a shortened BLyS mutein to induce and/orbind to antibodies which recognize the full-length or mature forms orthe extracellular domain of the polypeptide generally will be retainedwhen less than the majority of the residues of the full-length or matureor extracellular domain of the polypeptide are removed from theN-tenninus. Whether a particular polypeptide lacking N-terminal residuesof a complete polypeptide retains such immunologic activities canreadily be determined by routine methods described herein and otherwiseknown in the art. It is not unlikely that a BLyS mutein with a largenumber of deleted N-terminal amino acid residues may retain somefunctional (e.g., biological or immunogenic) activities. In fact,peptides composed of as few as six BLyS amino acid residues may oftenevoke an immune response.

[0122] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues deleted from theamino terminus of the predicted full-length amino acid sequence of theBLyS shown in SEQ ID NO:3228, up to the glycine residue at positionnumber 280 of the sequence shown SEQ ID NO:3228 and polynucleotidesencoding such polypeptides. In particular, the present inventionprovides antibodies that bind polypeptides comprising the amino acidsequence of residues n³-285 of the sequence shown in SEQ ID NO:3228,where n³ is an integer in the range of the amino acid position of aminoacid residues 1 to 280 of the amino acid sequence in SEQ ID NO:3228.

[0123] More in particular, the invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, an amino acidsequence selected from the group consisting of residues of D-2 to L-285;D-3 to L-285; S-4 to L-285; T-5 to L-285; E-6 to L-285; R-7 to L-285;E-8 to L-285; Q-9 to L-285; S-10 to L-285; R-11 to L-285; L-12 to L-285;T-13 to L-285; S-14 to L-285; C-15 to L-285; L-16 to L-285; K-17 toL-285; K-18 to L-285; R-19 to L-285; E-20 to L-285; E-21 to L-285; M-22to L-285; K-23 to L-285; L-24 to L-285; K-25 to L-285; E-26 to L-285;C-27 to L-285; V-28 to L-285; S-29 to L-285; I-30 to L-285; L-31 toL-285; P-32 to L-285; R-33 to L-285; K-34 to L-285; E-35 to L-285; S-36to L-285; P-37 to L-285; S-38 to L-285; V-39 to L-285; R-40 to L-285;S-41 to L-285; S-42 to L-285; K-43 to L-285; D-44 to L-285; G-45 toL-285; K-46 to L-285; L-47 to L-285; L-48 to L-285; A-49 to L-285; A-50to L-285; T-51 to L-285; L-52 to L-285; L-53 to L-285; L-54 to L-285;A-55 to L-285; L-56 to L-285; L-57 to L-285; S-58 to L-285; C-59 toL-285; C-60 to L-285; L-61 to L-285; T-62 to L-285; V-63 to L-285; V-64to L-285; S-65 to L-285; F-66 to L-285; Y-67 to L-285; Q-68 to L-285;V-69 to L-285; A-70 to L-285; A-71 to L-285; L-72 to L-285; Q-73 toL-285; G-74 to L-285; D-75 to L-285; L-76 to L-285; A-77 to L-285; S-78to L-285; L-79 to L-285; R-80 to L-285; A-81 to L-285; E-82 to L-285;L-83 to L-285; Q-84 to L-285; G-85 to L-285; H-86 to L-285; H-87 toL-285; A-88 to L-285; E-89 to L-285; K-90 to L-285; L-91 to L-285; P-92to L-285; A-93 to L-285; G-94 to L-285; A-95 to L-285; G-96 to L-285;A-97 to L-285; P-98 to L-285; K-99 to L-285; A-100 to L-285; G-101 toL-285; L-102 to L-285; E-103 to L-285; E-104 to L-285; A-105 to L-285;P-106 to L-285; A-107 to L-285; V-108 to L-285; T-109 to L-285; A-110 toL-285; G-111 to L-285; L-112 to L-285; K-113 to L-285; I-114 to L-285;F-115 to L-285; E-116 to L-285; P-117 to L-285; P-118 to L-285; A-119 toL-285; P-120 to L-285; G-121 to L-285; E-122 to L-285; G-123 to L-285;N-124 to L-285; S-125 to L-285; S-126 to L-285; Q-127 to L-285; N-128 toL-285; S-129 to L-285; R-130 to L-285; N-131 to L-285; K-132 to L-285;R-133 to L-285; A-134 to L-285; V-135 to L-285; Q-136 to L-285; G-137 toL-285; P-138 to L-285; E-139 to L-285; E-140 to L-285; T-141 to L-285;V-142 to L-285; T-143 to L-285; Q-144to L-285; D-145 to L-285; C-146 toL-285; L-147 to L-285; Q-148 to L-285; L-149 to L-285; E-150 to L-285;A-151 to L-285; D-152 to L-285; S-153 to L-285; E-154 to L-285; T-155 toL-285; P-156 to L-285; T-157 to L-285; I-158 to L-285; Q-159 to L-285;K-160 to L-285; G-161 to L-285; S-162 to L-285; Y-163 to L-285; T-164 toL-285; F-165 to L-285; V-166 to L-285; P-167 to L-285; W-168 to L-285;L-169 to L-285; L-170 to L-285; S-171 to L-285; F-172 to L-285; K-173 toL-285; R-174 to L-285; G-175 to L-285; S-176 to L-285; A-177 to L-285;L-178 to L-285; E-179 to L-285; E-180 to L-285; K-181 to L-285; E-182 toL-285; N-183 to L-285; K-184 to L-285; I-185 to L-285; L-186 to L-285;V-187 to L-285; K-188 to L-285; E-189 to L-285; T-190 to L-285; G-191 toL-285; Y-192 to L-285; F-193 to L-285; F-194 to L-285; I-195 to L-285;Y-196 to L-285; G-197 to L-285; Q-198 to L-285; V-199 to L-285; L-200 toL-285; Y-201 to L-285; T-202 to L-285; D-203 to L-285; K-204 to L-285;T-205 to L-285; Y-206 to L-285; A-207 to L-285; M-208 to L-285; G-209 toL-285; H-210 to L-285; L-211 to L-285; I-212 to L-285; Q-213 to L-285;R-214 to L-285; K-215 to L-285; K-216 to L-285; V-217 to L-285; H-218 toL-285; V-219 to L-285; F-220 to L-285; G-221 to L-285; D-222 to L-285;E-223 to L-285; L-224 to L-285; S-225 to L-285; L-226 to L-285; V-227 toL-285; T-228 to L-285; L-229 to L-285; F-230 to L-285; R-231 to L-285;C-232 to L-285; I-233 to L-285; Q-234 to L-285; N-235 to L-285; M-236 toL-285; P-237 to L-285; E-238 to L-285; T-239 to L-285; L-240 to L-285;P-241 to L-285; N-242 to L-285; N-243 to L-285; S-244 to L-285; C-245 toL-285; Y-246 to L-285; S-247 to L-285; A-248 to L-285; G-249 to L-285;I-250 to L-285; A-251 to L-285; K-252 to L-285; L-253 to L-285; E-254 toL-285; E-255 to L-285; G-256 to L-285; D-257 to L-285; E-258 to L-285;L-259 to L-285; Q-260 to L-285; L-261 to L-285; A-262 to L-285; I-263 toL-285; P-264 to L-285; R-265 to L-285; E-266 to L-285; N-267 to L-285;A-268 to L-285; Q-269 to L-285; I-270 to L-285; S-271 to L-285; L-272 toL-285; D-273 to L-285; G-274 to L-285; D-275 to L-285; V-276 to L-285;T-277 to L-285; F-278 to L-285; F-279 to L-285; and G-280 to L-285 ofSEQ ID NO:3228. The present invention is also directed to antibodiesthat bind BLyS polypeptides comprising, or alternatively, consisting of,a contiguous sequence of amino acid residues at least 80%, 85%, 90%,92%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence ofBLyS polypeptides described above.

[0124] Also as mentioned above, even if deletion of one or more aminoacids from the C-terminus of a protein results in modification or lossof one or more functional activities (e.g., biological activity) of theprotein, other functional activities may still be retained. Thus, theability of a shortened BLyS mutein to induce and/or bind to antibodieswhich recognize the complete or mature form or the extracellular domainof the polypeptide generally will be retained when less than themajority of the residues of the complete or mature form or theextracellular domain of the polypeptide are removed from the C-terminus.Whether a particular polypeptide lacking C-terminal residues of acomplete polypeptide retains such immunologic activities can readily bedetermined by routine methods described herein and otherwise known inthe art. It is not unlikely that a BLyS mutein with a large number ofdeleted C-terminal amino acid residues may retain some functional (e.g.,biological or immunogenic) activities. In fact, peptides composed of asfew as six BLyS amino acid residues may often evoke an immune response.

[0125] Accordingly, the present invention further provides in anotherembodiment, antibodies that bind polypeptides having one or moreresidues deleted from the carboxy terminus of the amino acid sequence ofthe BLyS shown in SEQ ID NO:3228, up to the glutamic acid residue atposition number 6, and polynucleotides encoding such polypeptides. Inparticular, the present invention provides antibodies that bindpolypeptides comprising the amino acid sequence of residues 1-m³ of SEQID NO:3228, where m³ is an integer in the range of the amino acidposition of amino acid residues 6-284 of the amino acid sequence in SEQID NO:3228.

[0126] More in particular, the invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, an amino acidsequence selected from the group consisting of residues M-1 to L-284;M-1 to K-283; M-1 to L-282; M-1 to A-281; M-1 to G-280; M-1 to F-279;M-1 to F-278; M-1 to T-277; M-1 to V-276; M-1 to D-275; M-1 to G-274;M-1 to D-273; M-1 to L-272; M-1 to S-271; M-1 to I-270; M-1 to Q-269;M-1 to A-268; M-1 to N-267; M-1 to E-266; M-1 to R-265; M-1 to P-264;M-1 to I-263; M-1 to A-262; M-1 to L-261; M-1 to Q-260; M-1 to L-259;M-1 to E-258; M-1 to D-257; M-1 to G-256; M-1 to E-255; M-1 to E-254;M-1 to L-253; M-1 to K-252; M-1 to A-251; M-1 to I-250; M-1 to G-249;M-1 to A-248; M-1 to S-247; M-1 to Y-246; M-1 to C-245; M-1 to S-244;M-1 to N-243; M-1 to N-242; M-1 to P-241; M-1 to L-240; M-1 to T-239;M-1 to E-238; M-1 to P-237; M-1 to M-236; M-1 to N-235; M-1 to Q-234;M-1 to I-233; M-1 to C-232; M-1 to R-231; M-1 to F-230; M-1 to L-229;M-1 to T-228; M-1 to V-227; M-1 to L-226; M-1 to S-225; M-1 to L-224;M-1 to E-223; M-1 to D-222; M-1 to G-221; M-1 to F-220; M-1 to V-219;M-1 to H-218; M-1 to V-217; M-1 to K-216; M-1 to K-215; M-1 to R-214;M-1 to Q-213; M-1 to I-212; M-1 to L-211; M-1 to H-210; M-1 to G-209;M-1 to M-208; M-1 to A-207; M-1 to Y-206; M-1 to T-205; M-1 to K-204;M-1 to D-203; M-1 to T-202; M-1 to Y-201; M-1 to L-200; M-1 to V-199;M-1 to Q-198; M-1 to G-197; M-1 to Y-196; M-1 to I-195; M-1 to F-194;M-1 to F-193; M-1 to Y-192; M-1 to G-191; M-1 to T-190; M-1 to E-189;M-1 to K-188; M-1 to V-187; M-1 to L-186; M-1 to K-185; M-1 to K-184;M-1 to N-183; M-1 to E-182; M-1 to K-181; M-1 to E-180; M-1 to E-179;M-1 to L-178; M-1 to A-177; M-1 to S-176; M-1 to G-175; M-1 to R-174;M-1 to K-273; M-1 to F-172; M-1 to S-171; M-1 to L-170; M-1 to L-169;M-1 to W-168; M-1 to P-167; M-1 to V-166; M-1 to F-165; M-1 to T-164;M-1 to Y-163; M-1 to S-162; M-1 to G-161; M-1 to K-160; M-1 to Q-159;M-1 to I-158; M-1 to T-157; M-1 to P-156; M-1 to T-155; M-1 to E-154;M-1 to S-153; M-1 to D-152; M-1 to A-151; M-1 to E-180; M-1 to L-149;M-1 to Q-148; M-1 to L-147; M-1 to C-146; M-1 to D-145; M-1 to Q-144;M-1 to T-143; M-1 to V-142; M-1 to T-141; M-1 to E-140; M-1 to E-139;M-1 to P-138; M-1 to G-137; M-1 to Q-136; M-1 to V-135; M-1 to A-134;M-1 to R-133; M-1 to K-132; M-1 to N-131; M-1 to R-130; M-1 to S-129;M-1 to N-128; M-1 to Q-127; M-1 to S-126; M-1 to S-125; M-1 to N-124;M-1 to G-123; M-1 to E-122; M-1 to G-121; M-1 to P-120; M-1 to A-119;M-1 to P-118; M-1 to P-117; M-1 to E-116; M-1 to F-115; M-1 to I-114;M-1 to K-113; M-1 to L-112; M-1 to G-111; M-1 to A-110; M-1 to T-109;M-1 to V-108; M-1 to A-107; M-1 to P-106; M-1 to A-105; M-1 to E-104;M-1 to E-103; M-1 to L-102; M-1 to G-101; M-1 to A-100; M-1 to K-99; M-1to P-98; M-1 to A-97; M-1 to G-96; M-1 to A-95; M-1 to G-94; M-1 toA-93; M-1 to P-92; M-1 to L-91; M-1 to K-90; M-1 to E-89; M-1 to A-88;M-1 to H-87; M-1 to H-86; M-1 to G-85; M-1 to Q-84; M-1 to L-83; M-1 toE-82; M-1 to A-81; M-1 to R-80; M-1 to L-79; M-1 to S-78; M-1 to A-77;M-1 to L-76; M-1 to D-75; M-1 to G-74; M-1 to Q-73; M-1 to L-72; M-1 toA-71; M-1 to A-70; M-1 to V-69; M-1 to Q-68; M-1 to Y-67; M-1 to F-66;M-1 to S-65; M-1 to V-64; M-1 to V-63; M-1 to T-62; M-1 to L-61; M-1 toC-60; M-1 to C-59; M-1 to S-58; M-1 to L-57; M-1 to L-56; M-1 to A-55;M-1 to L-54; M-1 to L-53; M-1 to L-52; M-1 to T-51; M-1 to A-50; M-1 toA-49; M-1 to L-48; M-1 to L-47; M-1 to K-46; M-1 to G-45; M-1 to D-44;M-1 to K-43; M-1 to S-42; M-1 to S-41; M-1 to R-40; M-1 to V-39; M-1 toS-38; M-1 to P-37; M-1 to S-36; M-1 to E-35; M-1 to K-34; M-1 to R-33;M-1 to P-32; M-1 to L-31; M-1 to I-30; M-1 to S-29; M-1 to V-28; M-1 toC-27; M-1 to E-26; M-1 to K-25; M-1 to L-24; M-1 to K-23; M-1 to M-22;M-1 to E-21; M-1 to E-20; M-1 to R-19; M-1 to K-18; M-1 to K-17; M-1 toL-16; M-1 to C-15; M-1 to S-14; M-1 to T-13; M-1 to L-12; M-1 to R-11;M-1 to S-10; M-1 to Q-9; M-1 to E-8; M-1 to R-7; and M-1 to E-6 of SEQID NO:3228. The present invention is also directed to antibodies thatbind BLyS polypeptides comprising, or alternatively, consisting of, acontiguous sequence of amino acid residues at least 80%, 85%, 90%, 92%,95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of BLySpolypeptides described above.

[0127] The invention also provides antibodies that bind polypeptideshaving one or more amino acids deleted from both the amino and thecarboxyl termini of a BLyS polypeptide, which may be described generallyas having residues n³-m³ of SEQ ID NO:3228, where n³ and m³ are integersas defined above.

[0128] Furthermore, since the predicted extracellular domain of the BLySpolypeptide of SEQ ID NO:3229 may itself elicit functional activity(e.g., biological activity), deletions of N- and C-terminal amino acidresidues from the predicted extracellular region of the polypeptide atpositions Gln-73 to Leu-266 of SEQ ID NO:3229 may retain some functionalactivity, such as, for example, ligand binding, to stimulation oflymphocyte (e.g., B cell) proliferation, differentiation, and/oractivation, modulation of cell replication, modulation of target cellactivities and/or immunogenicity. However, even if deletion of one ormore amino acids from the N-terminus of the predicted extracellulardomain of a BLyS polypeptide results in modification or loss of one ormore functional activities of the polypeptide, other functionalactivities may still be retained. Thus, the ability of the shortenedpolypeptides to induce and/or bind to antibodies which recognize thecomplete or mature or extracellular domains of the polypeptidesgenerally will be retained when less than the majority of the residuesof the complete or mature or extracellular domains of the polypeptidesare removed from the N-terminus. Whether a particular polypeptidelacking N-terminal residues of a complete polypeptide retains suchimmunologic activities can readily be determined by routine methodsdescribed herein and otherwise known in the art.

[0129] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues deleted from theamino terminus of the amino acid sequence of BLyS shown in SEQ IDNO:3229, up to the glycine residue at position number 261. Inparticular, the present invention provides antibodies that bindpolypeptides comprising the amino acid sequence of residues n⁴-266 ofSEQ ID NO:3229, where n⁴ is an integer in the range of the amino acidposition of amino acid residues 73-261 of the amino acid sequence in SEQID NO:3229, and 261 is the position of the first residue from theN-terminus of the predicted extracellular domain BLyS polypeptide (shownin SEQ ID NO:3229).

[0130] More in particular, in certain embodiments, the inventionprovides antibodies that bind polypeptides comprising, or alternativelyconsisting of, an amino acid sequence selected from the group consistingof residues of Q-73 to L-266; G-74 to L-266; D-75 to L-266; L-76 toL-266; A-77 to L-266; S-78 to L-266; L-79 to L-266; R-80 to L-266; A-81to L-266; E-82 to L-266; L-83 to L-266; Q-84 to L-266; G-85 to L-266;H-86 to L-266; H-87 to L-266; A-88 to L-266; E-89 to L-266; K-90 toL-266; L-91 to L-266; P-92 to L-266; A-93 to L-266; G-94 to L-266; A-95to L-266; G-96 to L-266; A-97 to L-266; P-98 to L-266; K-99 to L-266;A-100 to L-266; G-101 to L-266; L-102 to L-266; E-103 to L-266; E-104 toL-266; A-105 to L-266; P-106 to L-266; A-107 to L-266; V-108 to L-266;T-109 to L-266; A-110 to L-266; G-111 to L-266; L-112 to L-266; K-113 toL-266; I-114 to L-266; F-115 to L-266; E-116 to L-266; P-117 to L-266;P-118 to L-266; A-119 to L-266; P-120 to L-266; G-121 to L-266; E-122 toL-266; G-123 to L-266; N-124 to L-266; S-125 to L-266; S-126 to L-266;Q-127 to L-266; N-128 to L-266; S-129 to L-266; R-130 to L-266; N-131 toL-266; K-132 to L-266; R-133 to L-266; A-134 to L-266; V-135 to L-266;Q-136 to L-266; G-137 to L-266; P-138 to L-266; E-139 to L-266; E-140 toL-266; T-141 to L-266; G-142 to L-266; S-143 to L-266; Y-144 to L-266;T-145 to L-266; F-146 to L-266; V-147 to L-266; P-148 to L-266; W-149 toL-266; L-150 to L-266; L-151 to L-266; S-152 to L-266; F-153 to L-266;K-154 to L-266; R-155 to L-266; G-156 to L-266; S-157 to L-266; A-158 toL-266; L-159 to L-266; E-160 to L-266; E-161 to L-266; K-162 to L-266;E-163 to L-266; N-164 to L-266; K-165 to L-266; I-166 to L-266; L-167 toL-266; V-168 to L-266; K-169 to L-266; E-170 to L-266; T-171 to L-266;G-172 to L-266; Y-173 to L-266; F-174 to L-266; F-175 to L-266; I-176 toL-266; Y-177 to L-266; G-178 to L-266; Q-179 to L-266; V-180 to L-266;L-181 to L-266; Y-182 to L-266; T-183 to L-266; D-184 to L-266; K-185 toL-266; T-186 to L-266; Y-187 to L-266; A-188 to L-266; M-189 to L-266;G-190 to L-266; H-191 to L-266; L-192 to L-266; I-193 to L-266; Q-194 toL-266; R-195 to L-266; K-196 to L-266; K-197 to L-266; V-198 to L-266;H-199 to L-266; V-200 to L-266; F-201 to L-266; G-202 to L-266; D-203 toL-266; E-204 to L-266; L-205 to L-266; S-206 to L-266; L-207 to L-266;V-208 to L-266; T-209 to L-266; L-210 to L-266; F-211 to L-266; R-212 toL-266; C-213 to L-266; I-214 to L-266; Q-215 to L-266; N-216 to L-266;M-217 to L-266; P-218 to L-266; E-219 to L-266; T-220 to L-266; L-221 toL-266; P-222 to L-266; N-223 to L-266; N-224 to L-266; S-225 to L-266;C-226 to L-266; Y-227 to L-266; S-228 to L-266; A-229 to L-266; G-230 toL-266; I-231 to L-266; A-232 to L-266; K-233 to L-266; L-234 to L-266;E-235 to L-266; E-236 to L-266; G-237 to L-266; D-238 to L-266; E-239 toL-266; L-240 to L-266; Q-241 to L-266; L-242 to L-266; A-243 to L-266;I-244 to L-266; P-245 to L-266; R-246 to L-266; E-247 to L-266; N-248 toL-266; A-249 to L-266; Q-250 to L-266; I-251 to L-266; S-252 to L-266;L-253 to L-266; D-254 to L-266; G-255 to L-266; D-256 to L-266; V-257 toL-266; T-258 to L-266; F-259 to L-266; F-260 to L-266; and G-261 toL-266 of SEQ ID NO:3229. The present invention is also directed toantibodies that bind BLyS polypeptides comprising, or alternatively,consisting of, a contiguous sequence of amino acid residues at least80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the aminoacid sequence of BLyS polypeptides described above.

[0131] Similarly, deletions of C-terminal amino acid residues of thepredicted extracellular domain of BLyS up to the leucine residue atposition 79 of SEQ ID NO:3229 may retain some functional activity, suchas, for example, ligand binding, the ability to stimulate lymphocyte(e.g., B cell) proliferation, differentiation, and/or activation,modulation of cell replication, modulation of target cell activitiesand/or immunogenicity. Polypeptides having further C-terminal deletionsincluding Leu-79 of SEQ ID NO:3229 would not be expected to retainbiological activities.

[0132] However, even if deletion of one or more amino acids from theC-terminus of a polypeptide results in modification or loss of one ormore functional activities (e.g., biological activity) of thepolypeptide, other functional activities may still be retained. Thus,the ability of the shortened polypeptide to induce and/or bind toantibodies which recognize the complete, mature or extracellular formsof the polypeptide generally will be retained when less than themajority of the residues of the complete, mature or extracellular formsof the polypeptide are removed from the C-terminus. Whether a particularpolypeptide lacking C-terminal residues of the predicted extracellulardomain retains such immunologic activities can readily be determined byroutine methods described herein and otherwise known in the art.

[0133] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues from the carboxyterminus of the amino acid sequence of the predicted extracellulardomain of BLyS shown in SEQ ID NO:3229, up to the leucine residue atposition 79 of SEQ ID NO:3229. In particular, the present inventionprovides antibodies that bind polypeptides having the amino acidsequence of residues 73-m⁴ of the amino acid sequence in SEQ ID NO:3229,where m⁴ is any integer in the range of the amino acid position of aminoacid residues 79-265 of the amino acid sequence in SEQ ID NO:3229.

[0134] More in particular, in certain embodiments, the inventionprovides antibodies that bind polypeptides comprising, or alternativelyconsisting of, an amino acid sequence selected from the group consistingof residues Q-73 to L-265; Q-73 to K-264; Q-73 to L-263; Q-73 to A-262;Q-73 to G-261; Q-73 to F-260; Q-73 to F-259; Q-73 to T-258; Q-73 toV-257; Q-73 to D-256; Q-73 to G-255; Q-73 to D-254; Q-73 to L-253; Q-73to S-252; Q-73 to I-251; Q-73 to Q-250; Q-73 to A-249; Q-73 to N-248;Q-73 to E-247; Q-73 to R-246; Q-73 to P-245; Q-73 to I-244; Q-73 toA-243; Q-73 to L-242; Q-73 to Q-241; Q-73 to L-240; Q-73 to E-239; Q-73to D-238; Q-73 to G-237; Q-73 to E-236; Q-73 to E-235; Q-73 to L-234;Q-73 to K-233; Q-73 to A-232; Q-73 to I-231; Q-73 to G-230; Q-73 toA-229; Q-73 to S-228; Q-73 to Y-227; Q-73 to C-226; Q-73 to S-225; Q-73to N-224; Q-73 to N-223; Q-73 to P-222; Q-73 to L-221; Q-73 to T-220;Q-73 to E-219; Q-73 to P-218; Q-73 to M-217; Q-73 to N-216; Q-73 toQ-215; Q-73 to I-214; Q-73 to C-213; Q-73 to R-212; Q-73 to F-211; Q-73to L-210; Q-73 to T-209; Q-73 to V-208; Q-73 to L-207; Q-73 to S-206;Q-73 to L-205; Q-73 to E-204; Q-73 to D-203; Q-73 to G-202; Q-73 toF-201; Q-73 to V-200; Q-73 to H-199; Q-73 to V-198; Q-73 to K-197; Q-73to K-196; Q-73 to R-195; Q-73 to Q-194; Q-73 to I-193; Q-73 to L-192;Q-73 to H-191; Q-73 to G-190; Q-73 to Q-7389; Q-73 to A-188; Q-73 toY-187; Q-73 to T-186; Q-73 to K-185; Q-73 to D-184; Q-73 to T-183; Q-73to Y-182; Q-73 to L-181; Q-73 to V-180; Q-73 to Q-179; Q-73 to G-178;Q-73 to Y-177; Q-73 to I-176; Q-73 to F-175; Q-73 to F-174; Q-73 toY-173; Q-73 to G-172; Q-73 to T-171; Q-73 to E-170; Q-73 to K-169; Q-73to V-168; Q-73 to L-167; Q-73 to I-166; Q-73 to K-165; Q-73 to N-164;Q-73 to E-163; Q-73 to K-162; Q-73 to E-161; Q-73 to E-160; Q-73 toL-159; Q-73 to A-158; Q-73 to S-157; Q-73 to G-156; Q-73 to R-155; Q-73to K-154; Q-73 to F-153; Q-73 to S-152; Q-73 to L-151; Q-73 to L-150;Q-73 to W-149; Q-73 to P-148; Q-73 to V-147; Q-73 to F-146; Q-73 toT-145; Q-73 to Y-144; Q-73 to S-143; Q-73 to G-142; Q-73 to T-141; Q-73to E-140; Q-73 to E-139; Q-73 to P-138; Q-73 to G-137; Q-73 to Q-136;Q-73 to V-135; Q-73 to A-134; Q-73 to R-133; Q-73 to K-132; Q-73 toN-131; Q-73 to R-130; Q-73 to S-129; Q-73 to N-128; Q-73 to Q-127; Q-73to S-126; Q-73 to S-125; Q-73 to N-124; Q-73 to G-123; Q-73 to E-122;Q-73 to G-121; Q-73 to P-120; Q-73 to A-119; Q-73 to P-118; Q-73 toP-117; Q-73 to E-116; Q-73 to F-115; Q-73 to I-114; Q-73 to K-113; Q-73to L-112; Q-73 to G-111; Q-73 to A-110; Q-73 to T-109; Q-73 to V-108;Q-73 to A-107; Q-73 to P-106; Q-73 to A-105; Q-73 to E-104; Q-73 toE-103; Q-73 to L-102; Q-73 to G-101; Q-73 to A-100; Q-73 to K-99; Q-73to P-98; Q-73 to A-97; Q-73 to G-96; Q-73 to A-95; Q-73 to G-94; Q-73 toA-93; Q-73 to P-92; Q-73 to L-91; Q-73 to K-90; Q-73 to E-89; Q-73 toA-88; Q-73 to H-87; Q-73 to H-86; Q-73 to G-85; Q-73 to Q-84; Q-73 toL-83; Q-73 to E-82; Q-73 to A-81; Q-73 to R-80; Q-73 to L-79; and Q-73to S-78 of SEQ ID NO:3229. The present invention is also directed toantibodies that bind BLyS polypeptides comprising, or alternatively,consisting of, a contiguous sequence of amino acid residues at least80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the aminoacid sequence of BLyS polypeptides described above.

[0135] The invention also provides polypeptides having one or more aminoacids deleted from both the amino and the carboxyl termini of thepredicted extracellular domain of BLyS, which may be described generallyas having residues n⁴-m⁴ of SEQ ID NO:3229 where n⁴ and m⁴ are integersas defined above.

[0136] In another embodiment, antibodies of the present invention bindpolypeptides consisting of a portion of the extracellular domain of theBLyS amino acid sequence encoded by the cDNA clone contained in thedeposit having ATCC Accession No. 203518, where this portion excludesfrom 1 to about 260 amino acids from the amino terminus of theextracellular domain of the amino acid sequence encoded by CDNA clonecontained in the deposit having ATCC Accession No. 203518, or from 1 toabout 187 amino acids from the carboxy terminus of the extracellulardomain of the amino acid sequence encoded by cDNA clone contained in thedeposit having ATCC Accession No. 203518, or any combination of theabove amino terminal and carboxy terminal deletions, of the entireextracellular domain of the amino acid sequence encoded by the CDNAclone contained in the deposit having ATCC Accession No. 203518.

[0137] As mentioned above, even if deletion of one or more amino acidsfrom the N-terminus of a polypeptide results in modification or loss ofone or more functional activities (e.g., biological activity) of thepolypeptide, other functional activities may still be retained. Thus,the ability of a shortened BLyS polypeptide to induce and/or bind toantibodies which recognize the full-length or mature forms or theextracellular domain of the polypeptide generally will be retained whenless than the majority of the residues of the full-length or mature orextracellular domain of the polypeptide are removed from the N-terminus.Whether a particular polypeptide lacking N-terminal residues of acomplete polypeptide retains such immunologic activities can readily bedetermined by routine methods described herein and otherwise known inthe art. It is not unlikely that a BLyS mutein with a large number ofdeleted N-terminal amino acid residues may retain functional (e.g.,immunogenic) activities. In fact, peptides composed of as few as sixBLyS amino acid residues may often evoke an immune response.

[0138] Accordingly, the present invention further provides antibodiesthat bind polypeptides having one or more residues deleted from theamino terminus of the predicted full-length amino acid sequence of theBLyS polypeptide shown in SEQ ID NO:3229, up to the glycine residue atposition number 261 of the sequence shown SEQ ID NO:3229 andpolynucleotides encoding such polypeptides. In particular, the presentinvention provides antibodies that bind polypeptides comprising theamino acid sequence of residues n⁵-266 of the sequence shown in SEQ IDNO:3229, where n⁵ is an integer in the range of the amino acid positionof amino acid residues 1 to 261 of the amino acid sequence in SEQ IDNO:3229.

[0139] More in particular, the invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, an amino acidsequence selected from the group consisting of residues of D-2 to L-266;D-3 to L-266; S-4 to L-266; T-5 to L-266; E-6 to L-266; R-7 to L-266;E-8 to L-266; Q-9 to L-266; S-10 to L-266; R-11 to L-266; L-12 to L-266;T-13 to L-266; S-14 to L-266; C-15 to L-266; L-16 to L-266; K-17 toL-266; K-18 to L-266; R-19 to L-266; E-20 to L-266; E-21 to L-266; M-22to L-266; K-23 to L-266; L-24 to L-266; K-25 to L-266; E-26 to L-266;C-27 to L-266; V-28 to L-266; S-29 to L-266; I-30 to L-266; L-31 toL-266; P-32 to L-266; R-33 to L-266; K-34 to L-266; E-35 to L-266; S-36to L-266; P-37 to L-266; S-38 to L-266; V-39 to L-266; R-40 to L-266;S-41 to L-266; S-42 to L-266; K-43 to L-266; D-44 to L-266; G-45 toL-266; K-4 6 to L-266; L-47 to L-266; L-48 to L-266; A-49 to L-266; A-50to L-266; T-51 to L-266; L-52 to L-266; L-53 to L-266; L-54 to L-266;A-55 to L-266; L-56 to L-266; L-57 to L-266; S-58 to L-266; C-59 toL-266; C-60 to L-266; L-61 to L-266; T-62 to L-266; V-63 to L-266; V-64to L-266; S-65 to L-266; F-66 to L-266; Y-67 to L-266; Q-68 to L-266;V-69 to L-266; A-70 to L-266; A-71 to L-266; L-72 to L-266; Q-73 toL-266; G-74 to L-266; D-75 to L-266; L-76 to L-266; A-77 to L-266; S-78to L-266; L-79 to L-266; R-80 to L-266; A-81 to L-266; E-82 to L-266;L-83 to L-266; Q-84 to L-266; G-85 to L-266; H-86 to L-266; H-87 toL-266; A-88 to L-266; E-89 to L-266; K-90 to L-266; L-91 to L-266; P-92to L-266; A-93 to L-266; G-94 to L-266; A-95 to L-266; G-96 to L-266;A-97 to L-266; P-98 to L-266; K-99 to L-266; A-100 to L-266; G-101 toL-266; L-102 to L-266; E-103 to L-266; E-104 to L-266; A-105 to L-266;P-106 to L-266; A-107 to L-266; V-108 to L-266; T-109 to L-266; A-110 toL-266; G-111 to L-266; L-112 to L-266; K-113 to L-266; I-114 to L-266;F-115 to L-266; E-116 to L-266; P-117 to L-266; P-118 to L-266; A-119 toL-266; P-120 to L-266; G-121 to L-266; E-122 to L-266; G-123 to L-266;N-124 to L-266; S-125 to L-266; S-126 to L-266; Q-127 to L-266; N-128 toL-266; S-129 to L-266; R-130 to L-266; N-131 to L-266; K-132 to L-266;R-133 to L-266; A-134 to L-266; V-135 to L-266; Q-136 to L-266; G-137 toL-266; P-138 to L-266; E-139 to L-266; E-140 to L-266; T-141 to L-266;G-142 to L-266; S-143 to L-266; Y-144 to L-266; T-145 to L-266; F-146 toL-266; V-147 to L-266; P-148 to L-266; W-149 to L-266; L-150 to L-266;L-151 to L-266; S-152 to L-266; F-153 to L-266; K-154 to L-266; R-155 toL-266; G-156 to L-266; S-157 to L-266; A-158 to L-266; L-159 to L-266;E-160 to L-266; E-161 to L-266; K-162 to L-266; E-163 to L-266; N-164 toL-266; K-165 to L-266; I-166 to L-266; L-167 to L-266; V-168 to L-266;K-169 to L-266; E-170 to L-266; T-171 to L-266; G-172 to L-266; Y-173 toL-266; F-174 to L-266; F-175 to L-266; I-176 to L-266; Y-177 to L-266;G-178 to L-266; Q-179 to L-266; V-180 to L-266; L-181 to L-266; Y-182 toL-266; T-183 to L-266; D-184 to L-266; K-185 to L-266; T-186 to L-266;Y-187 to L-266; A-188 to L-266; M-189 to L-266; G-190 to L-266; H-191 toL-266; L-192 to L-266; I-193 to L-266; Q-194 to L-266; R-195 to L-266;K-196 to L-266; K-197 to L-266; V-198 to L-266; H-199 to L-266; V-200 toL-266; F-201 to L-266; G-202 to L-266; D-203 to L-266; E-204 to L-266;L-205 to L-266; S-206 to L-266; L-207 to L-266; V-208 to L-266; T-209 toL-266; L-210 to L-266; F-211 to L-266; R-212 to L-266; C-213 to L-266;I-214 to L-266; Q-215 to L-266; N-216 to L-266; M-217 to L-266; P-218 toL-266; E-219 to L-266; T-220 to L-266; L-221 to L-266; P-222 to L-266;N-223 to L-266; N-224 to L-266; S-225 to L-266; C-226 to L-266; Y-227 toL-266; S-228 to L-266; A-229 to L-266; G-230 to L-266; I-231 to L-266;A-232 to L-266; K-233 to L-266; L-234 to L-266; E-235 to L-266; E-236 toL-266; G-237 to L-266; D-238 to L-266; E-239 to L-266; L-240 to L-266;Q-241 to L-266; L-242 to L-266; A-243 to L-266; I-244 to L-266; P-245 toL-266; R-246 to L-266; E-247 to L-266; N-248 to L-266; A-249 to L-266;Q-250to L-266; I-251 to L-266; S-252 to L-266; L-253 to L-266; D-254 toL-266; G-255 to L-266; D-256 to L-266; V-257 to L-266; T-258 to L-266;F-259 to L-266; F-260 to L-266; and G-261 to L-266 of SEQ ID NO:3229.The present invention is also directed to antibodies that bind BLySpolypeptides comprising, or alternatively, consisting of, a contiguoussequence of amino acid residues at least 80%, 85%, 90%, 92%, 95%, 96%,97%, 98% or 99% identical to the amino acid sequence of BLySpolypeptides described above.

[0140] Also as mentioned above, even if deletion of one or more aminoacids from the C-terminus of a protein results in modification or lossof one or more functional activities (e.g., biological activities) ofthe protein, other functional activities may still be retained. Thus,the ability of a shortened BLyS mutein to induce and/or bind toantibodies which recognize the complete or mature form or theextracellular domain of the polypeptide generally will be retained whenless than the majority of the residues of the complete or mature form orthe extracellular domain of the polypeptide are removed from theC-terminus. Whether a particular polypeptide lacking C-terminal residuesof a complete polypeptide retains such immunologic activities canreadily be determined by routine methods described herein and otherwiseknown in the art. It is not unlikely that a BLyS mutein with a largenumber of deleted C-terminal amino acid residues may retain somefunctional (e.g., immunogenic) activities. In fact, peptides composed ofas few as six BLyS amino acid residues may often evoke an immuneresponse.

[0141] Accordingly, the present invention further provides in anotherembodiment, antibodies that bind polypeptides having one or moreresidues deleted from the carboxy terminus of the amino acid sequence ofthe BLyS shown in SEQ ID NO:3229, up to the glutamic acid residue atposition number 6, and polynucleotides encoding such polypeptides. Inparticular, the present invention provides antibodies that bindpolypeptides comprising the amino acid sequence of residues 1-m⁵ of SEQID NO:3229, where m⁵ is an integer in the range of the amino acidposition of amino acid residues 6 to 265 in the amino acid sequence ofSEQ ID NO:3229.

[0142] More in particular, the invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, an amino acidsequence selected from the group consisting of residues M-1 to L-265;M-1 to K-264; M-1 to L-263; M-1 to A-262; M-1 to G-261; M-1 to F-260;M-1 to F-259; M-1 to T-258; M-1 to V-257; M-1 to D-256; M-1 to G-255;M-1 to D-254; M-1 to L-253; M-1 to S-252; M-1 to I-251; M-1 to Q-250;M-1 to A-249; M-1 to N-248; M-1 to E-247; M-1 to R-246; M-1 to P-245;M-1 to I-244; M-1 to A-243; M-1 to L-242; M-1 to Q-241; M-1 to L-240;M-1 to E-239; M-1 to D-238; M-1 to G-237; M-1 to E-236; M-1 to E-235;M-1 to L-234; M-1 to K-233; M-1 to A-232; M-1 to I-231; M-1 to G-230;M-1 to A-229; M-1 to S-228; M-1 to Y-227; M-1 to C-226; M-1 to S-225;M-1 to N-224; M-1 to N-223; M-1 to P-222; M-1 to L-221; M-1 to T-220;M-1 to E-219; M-1 to P-218; M-1 to M-217; M-1 to N-216; M-1 to Q-215;M-1 to I-214; M-1 to C-213; M-1 to R-212; M-1 to F-211; M-1 to L-210;M-1 to T-209; M-1 to V-208; M-1 to L-207; M-1 to S-206; M-1 to L-205;M-1 to E-204; M-1 to D-203; M-1 to G-202; M-1 to F-201; M-1 to V-200;M-1 to H-199; M-1 to V-198; M-1 to K-197; M-1 to K-196; M-1 to R-195;M-1 to Q-194; M-1 to I-193; M-1 to L-192; M-1 to H-191; M-1 to G-190;M-1 to M-189; M-1 to A-188; M-1 to Y-187; M-1 to T-186; M-1 to K-185;M-1 to D-184; M-1 to T-183; M-1 to Y-182; M-1 to L-181; M-1 to V-180;M-1 to Q-179; M-1 to G-178; M-1 to Y-177; M-1 to I-176; M-1 to F-175;M-1 to F-174; M-1 to Y-173; M-1 to G-172; M-1 to T-171; M-1 to E-170;M-1 to K-169; M-1 to V-168; M-1 to L-167; M-1 to I-166; M-1 to K-165;M-1 to N-164; M-1 to E-163; M-1 to K-162; M-1 to E-161; M-1 to E-160;M-1 to L-159; M-1 to A-158; M-1 to S-157; M-1 to G-156; M-1 to R-155;M-1 to K-154; M-1 to F-153; M-1 to S-152; M-1 to L-151; M-1 to L-150;M-1 to W-149; M-1 to P-148; M-1 to V-147; M-1 to F-146; M-1 to T-145;M-1 to Y-144; M-1 to S-143; M-1 to G-142; M-1 to T-141; M-1 to E-140;M-1 to E-139; M-1 to P-138; M-1 to G-137; M-1 to Q-136; M-1 to V-135;M-1 to A-134; M-1 to R-133; M-1 to K-132; M-1 to N-131; M-1 to R-130;M-1 to S-129; M-1 to N-128; M-1 to Q-127; M-1 to S-126; M-1 to S-125;M-1 to N-124; M-1 to G-123; M-1 to E-122; M-1 to G-121; M-1 to P-120;M-1 to A-119; M-1 to P-118; M-1 to P-117; M-1 to E-116; M-1 to F-115;M-1 to I-114; M-1 to K-113; M-1 to L-112; M-1 to G-111; M-1 to A-110;M-1 to T-109; M-1 to V-108; M-1 to A-107; M-1 to P-106; M-1 to A-105;M-1 to E-104; M-1 to E-103; M-1 to L-102; M-1 to G-101; M-1 to A-100;M-1 to K-99; M-1 to P-98; M-1 to A-97; M-1 to G-96; M-1 to A-95; M-1 toG-94; M-1 to A-93; M-1 to P-92; M-1 to L-91; M-1 to K-90; M-1 to E-89;M-1 to A-88; M-1 to H-87; M-1 to H-86; M-1 to G-85; M-1 to Q-84; M-1 toL-83; M-1 to E-82; M-1 to A-81; M-1 to R-80; M-1 to L-79; M-1 to S-78;M-1 to A-77; M-1 to L-76; M-1 to D-75; M-1 to G-74; M-1 to Q-73; M-1 toL-72; M-1 to A-71; M-1 to A-70; M-1 to V-69; M-1 to Q-68; M-1 to Y-67;M-1 to F-66; M-1 to S-65; M-1 to V-64; M-1 to V-63; M-1 to T-62; M-1 toL-61; M-1 to C-60; M-1 to C-59; M-1 to S-58; M-1 to L-57; M-1 to L-56;M-1 to A-55; M-1 to L-54; M-1 to L-53; M-1 to L-52; M-1 to T-51; M-1 toA-50; M-1 to A-49; M-1 to L-48; M-1 to L-47; M-1 to K-46; M-1 to G-45;M-1 to D-44; M-1 to K-43; M-1 to S-42; M-1 to S-41; M-1 to R-40; M-1 toV-39; M-1 to S-38; M-1 to P-37; M-1 to S-36; M-1 to E-35; M-1 to K-34;M-1 to R-33; M-1 to P-32; M-1 to L-31; M-1 to I-30; M-1 to S-29; M-1 toV-28; M-1 to C-27; M-1 to E-26; M-1 to K-25; M-1 to L-24; M-1 to K-23;M-1 to M-22; M-1 to E-21; M-1 to E-20; M-1 to R-19; M-1 to K-18; M-1 toK-17; M-1 to L-16; M-1 to C-15; M-1 to S-14; M-1 to T-13; M-1 to L-12;M-1 to R-11; M-1 to S-10; M-1 to Q-9; M-1 to E-8; M-1 to R-7; and M-1 toE-6 of SEQ ID NO:3229. The present invention is also directed toantibodies that bind BLyS polypeptides comprising, or alternatively,consisting of, a contiguous sequence of amino acid residues at least80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the aminoacid sequence of BLyS polypeptides described above.

[0143] The invention also provides antibodies that bind polypeptideshaving one or more amino acids deleted from both the amino and thecarboxyl termini of a BLyS polypeptide, which may be described generallyas having residues n⁵-m⁵ of SEQ ID NO:3229, where n⁵ and m⁵ are integersas defined above.

[0144] In additional embodiments, the present invention providesantibodies that bind polypeptides comprising the amino acid sequence ofresidues 134-m⁶ of SEQ ID NO:3228, where m⁶ is an integer from 140 to285, corresponding to the position of the amino acid residue in SEQ IDNO:3228. For example, the invention provides antibodies that bindpolypeptides comprising, or alternatively consisting of, an amino acidsequence selected from the group consisting of residues A-134 toLeu-285; A-134 to L-284; A-134 to K-283; A-134 to L-282; A-134 to A-281;A-134 to G-280; A-134 to F-279; A-134 to F-278; A-134 to T-277; A-134 toV-276; A-134 to D-275; A-134 to G-274; A-134 to D-273; A-134 to L-272;A-134 to S-271; A-134 to I-270; A-134 to Q-269; A-134 to A-268; A-134 toN-267; A-134 to E-266; A-134 to R-265; A-134 to P-264; A-134 to I-263;A-134 to A-262; A-134 to L-261; A-134 to Q-260; A-134 to L-259; A-134 toE-258; A-134 to D-257; A-134 to G-256; A-134 to E-255; A-134 to E-254;A-134 to L-253; A-134 to K-252; A-134 to A-251; A-134 to I-250; A-134 toG-249; A-134 to A-248; A-134 to S-247; A-134 to Y-246; A-134 to C-245;A-134 to S-244; A-134 to N-243; A-134 to N-242; A-134 to P-241; A-134 toL-240; A-134 to T-239; A-134 to E-238; A-134 to P-237; A-134 to M-236;A-134 to N-235; A-134 to Q-234; A-134 to I-233; A-134 to C-232; A-134 toR-231; A-134 to F-230; A-134 to L-229; A-134 to T-228; A-134 to V-227;A-134 to L-226; A-134 to S-225; A-134 to L-224; A-134 to E-223; A-134 toD-222; A-134 to G-221; A-134 to F-220; A-134 to V-219; A-134 to H-218;A-134 to V-217; A-134 to K-216; A-134 to K-215; A-134 to R-214; A-134 toQ-213; A-134 to I-212; A-134 to L-211; A-134 to H-210; A-134 to G-209;A-134 to M-208; A-134 to A-207; A-134 to Y-206; A-134 to T-205; A-134 toK-204; A-134 to D-203; A-134 to T-202; A-134 to Y-201; A-134 to L-200;A-134 to V-199; A-134 to Q-198; A-134 to G-197; A-134 to Y-196; A-134 toI-195; A-134 to F-194; A-134 to F-193; A-134 to Y-192; A-134 to G-191;A-134 to T-190; A-134 to E-189; A-134 to K-188; A-134 to V-187; A-134 toL-186; A-134 to I-185; A-134 to K-184; A-134 to N-183; A-134 to E-182;A-134 to K-181; A-134 to E-180; A-134 to E-179; A-134 to L-178; A-134 toA-177; A-134 to S-176; A-134 to G-175; A-134 to R-174; A-134 to K-173;A-134 to F-172; A-134 to S-171; A-134 to L-170; A-134 to L-169; A-134 toW-168; A-134 to P-167; A-134 to V-166; A-134 to F-165; A-134 to T-164;A-134 to Y-163; A-134 to S-162; A-134 to G-161; A-134 to K-160; A-134 toQ-159; A-134 to I-158; A-134 to T-157; A-134 to P-156; A-134 to T-155;A-134 to E-154; A-134 to S-153; A-134 to D-152; A-134 to A-151; A-134 toI-150; A-134 to L-149; A-134 to Q-148; A-134 to L-147; A-134 to C-146;A-134 to D-145; A-134 to Q-144; A-134 to T-143; A-134 to V-142; A-134 toT-141; and A-134 to E-140 of SEQ ID NO:3228. The present invention isalso directed to antibodies that bind BLyS polypeptides comprising, oralternatively, consisting of, a contiguous sequence of amino acidresidues at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99%identical to the amino acid sequence of BLyS polypeptides describedabove.

[0145] In additional embodiments, antibodies of the present inventionmay bind polypeptide fragments comprising, or alternatively consistingof, an amino acid sequence selected from the group consisting ofresidues: M-1 to C-15; D-2 to L-16; D-3 to K-17; S-4 to K-18; T-5 toR-19; E-6 to E-20; R-7 to E-21; E-8 to M-22; Q-9 to K-23; S-10 to L-24;R-11 to K-25; L-12 to E-26; T-13 to C-27; S-14 to V-28; C-15 to S-29;L-16 to I-30; K-17 to L-31; K-18 to P-32; R-19 to R-33; E-20 to K-34;E-21 to E-35; M-22 to S-36; K-23 to P-37; L-24 to S-38; K-25 to V-39;E-26 to R-40; C-27 to S-41; V-28 to S-42; S-29 to K-43; I-30 to D-44;L-31 to G-45; P-32 to K-46; R-33 to L-47; K-34 to L-48; E-35 to A-49;S-36 to A-50; P-37 to T-51; S-38 to L-52; V-39 to L-53; R-40 to L-54;S-41 to A-55; S-42 to L-56; K-43 to L-57; D-44 to S-58; G-45 to C-59;K-46 to C-60; L-47 to L-61; L-48 to T-62; A-49 to V-63; A-50 to V-64;T-51 to S-65; L-52 to F-66; L-53 to Y-67; L-54 to Q-68; A-55 to V-69;L-56 to A-70; L-57 to A-71; S-58 to L-72; C-59 to Q-73; C-60 to G-74;L-61 to D-75; T-62 to L-76; V-63 to A-77; V-64 to S-78; S-65 to L-79;F-66 to R-80; Y-67 to A-81; Q-68 to E-82; V-69 to L-83; A-70 to Q-84;A-71 to G-85; L-72 to H-86; Q-73 to H-87; G-74 to A-88; D-75 to E-89;L-76 to K-90; A-77 to L-91; S-78 to P-92; L-79 to A-93; R-80 to G-94;A-81 to A-95; E-82 to G-96; L-83 to A-97; Q-84 to P-98; G-85 to K-99;H-86 to A-100; H-87 to G-101; A-88 to L-102; E-89 to E-103; K-90 toE-104; L-91 to A-105; P-92 to P-106; A-93 to A-107; G-94 to V-108; A-95to T-109; G-96 to A-110; A-97 to G-111; P-98 to L-112; K-99 to K-113;A-100 to I-114; G-101 to F-115; L-102 to E-116; E-103 to P-117; E-104 toP-118; A-105 to A-119; P-106 to P-120; A-107 to G-121; V-108 to E-122;T-109 to G-123; A-10 to N-124; G-11 to S-125; L-112 to S-126; K-113 toQ-127; I-114 to N-128; F-115 to S-129; E-116 to R-130; P-117 to N-131;P-118 to K-132; A-119 to R-133; P-120 to A-134; G-121 to V-135; E-122 toQ-136; G-123 to G-137; N-124 to P-138; S-125 to E-139; S-126 to E-140;Q-127 to T-141; N-128 to V-142; S-129 to T-143; R-130 to Q-144; N-131 toD-145; K-132 to C-146; R-133 to L-147; A-134 to Q-148; V-135 to L-149;Q-136 to I-150; G-137 to A-151; P-138 to D-152; E-139 to S-153; E-140 toE-154; T-141 to T-155; V-142 to P-156; T-143 to T-157; Q-144 to I-158;D-145 to Q-159; C-146 to K-160; L-147 to G-161; Q-148 to S-162; L-149 toY-163; I-150 to T-164; A-151 to F-165; D-152 to V-166; S-153 to P-167;E-154 to W-168; T-155 to L-169; P-156 to L-170; T-157 to S-171; I-158 toF-172; Q-159 to K-173; K-160 to R-174; G-161 to G-175; S-162 to S-176;Y-163 to A-177; T-164 to L-178; F-165 to E-179; V-166 to E-180; P-167 toK-181; W-168 to E-182; L-169 to N-183; L-170 to K-184; S-171 to I-185;F-172 to L-186; K-173 to V-187; R-174 to K-188; G-175 to E-189; S-176 toT-190; A-177 to G-191; L-178 to Y-192; E-179 to F-193; E-180 to F-194;K-181 to I-195; E-182 to Y-196; N-183 to G-197; K-184 to Q-198; I-185 toV-199; L-186 to L-200; V-187 to Y-201; K-188 to T-202; E-189 to D-203;T-190 to K-204; G-191 to T-205; Y-192 to Y-206; F-193 to A-207; F-194 toM-208; I-195 to G-209; Y-196 to H-210; G-197 to L-211; Q-198 to I-212;V-199 to Q-213; L-200 to R-214; Y-201 to K-215; T-202 to K-216; D-203 toV-217; K-204 to H-218; T-205 to V-219; Y-206 to F-220; A-207 to G-221;M-208 to D-222; G-209 to E-223; H-210 to L-224; L-211 to S-225; I-212 toL-226; Q-213 to V-227; R-214 to T-228; K-215 to L-229; K-216 to F-230;V-217 to R-231; H-218 to C-232; V-219 to I-233; F-220 to Q-234; G-221 toN-235; D-222 to M-236; E-223 to P-237; L-224 to E-238; S-225 to T-239;L-226 to L-240; V-227 to P-241; T-228 to N-242; L-229 to N-243; F-230 toS-244; R-231 to C-245; C-232 to Y-246; I-233 to S-247; Q-234 to A-248;N-235 to G-249; M-236 to I-250; P-237 to A-251; E-238 to K-252; T-239 toL-253; L-240 to E-254; P-241 to E-255; N-242 to G-256; N-243 to D-257;S-244 to E-258; C-245 to L-259; Y-246 to Q-260; S-247 to L-261; A-248 toA-262; G-249 to I-263; I-250 to P-264; A-251 to R-265; K-252 to E-266;L-253 to N-267; E-254 to A-268; E-255 to Q-269; G-256 to I-270; D-257 toS-271; E-258 to L-272; L-259 to D-273; Q-260 to G-274; L-261 to D-275;A-262 to V-276; I-263 to T-277; P-264 to F-278; R-265 to F-279; E-266 toG-280; N-267 to A-281; A-268 to L-282; Q-269 to K-283; I-270 to L-284;and S-271 to L-285 of SEQ ID NO:3228. The present invention is alsodirected to antibodies that bind BLyS polypeptides comprising, oralternatively, consisting of, a contiguous sequence of amino acidresidues at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99%identical to the amino acid sequence of BLyS polypeptides describedabove.

[0146] In additional embodiments, antibodies of the present inventionmay bind polypeptide fragments comprising, or alternatively consistingof, an amino acid sequence selected from the group consisting ofresidues: M-1 to C-15; D-2 to L-16; D-3 to K-17; S-4 to K-18; T-5 toR-19; E-6 to E-20; R-7 to E-21; E-8 to M-22; Q-9 to K-23; S-10 to L-24;R-11 to K-25; L-12 to E-26; T-13 to C-27; S-14 to V-28; C-15 to S-29;L-16 to I-30; K-17 to L-31; K-18 to P-32; R-19 to R-33; E-20 to K-34;E-21 to E-35; M-22 to S-36; K-23 to P-37; L-24 to S-38; K-25 to V-39;E-26 to R-40; C-27 to S-41; V-28 to S-42; S-29 to K-43; I-30 to D-44;L-31 to G-45; P-32 to K-46; R-33 to L-47; K-34 to L-48; E-35 to A-49;S-36 to A-50; P-37 to T-51; S-38 to L-52; V-39 to L-53; R-40 to L-54;S-41 to A-55; S-42 to L-56; K-43 to L-57; D-44 to S-58; G-45 to C-59;K-46 to C-60; L-47 to L-61; L-48 to T-62; A-49 to V-63; A-50 to V-64;T-51 to S-65; L-52 to F-66; L-53 to Y-67; L-54 to Q-68; A-55 to V-69;L-56 to A-70; L-57 to A-71; S-58 to L-72; C-59 to Q-73; C-60 to G-74;L-61 to D-75; T-62 to L-76; V-63 to A-77; V-64 to S-78; S-65 to L-79;F-66 to R-80; Y-67 to A-81; Q-68 to E-82; V-69 to L-83; A-70 to Q-84;A-71 to G-85; L-72 to H-86; Q-73 to H-87; G-74 to A-88; D-75 to E-89;L-76 to K-90; A-77 to L-91; S-78 to P-92; L-79 to A-93; R-80 to G-94;A-81 to A-95; E-82 to G-96; L-83 to A-97; Q-84 to P-98; G-85 to K-99;H-86 to A-100; H-87 to G-101; A-88 to L-102; E-89 to E-103; K-90 toE-104; L-91 to A-105; P-92 to P-106; A-93 to A-107; G-94 to V-108; A-95to T-109; G-96 to A-110; A-97 to G-111; P-98 to L-112; K-99 to K-113;A-100 to I-114; G-101 to F-115; L-102 to E-116; E-103 to P-117; E-104 toP-118; A-105 to A-119; P-106 to P-120; A-107 to G-121; V-108 to E-122;T-109 to G-123; A-110 to N-124; G-111 to S-125; L-112 to S-126; K-113 toQ-127; I-114 to N-128; F-115 to S-129; E-116 to R-130; P-117 to N-131;P-118 to K-132; A-119 to R-133; P-120 to A-134; G-121 to V-135; E-122 toQ-136; G-123 to G-137; N-124 to P-138; S-125 to E-139; S-126 to E-140;Q-127 to T-141; N-128 to G-142; S-129 to S-143; R-130 to Y-144; N-131 toT-145; K-132 to F-146; R-133 to V-147; A-134 to P-148; V-135 to W-149;Q-136 to L-150; G-137 to L-151; P-138 to S-152; E-139 to F-153; E-140 toK-154; T-141 to R-155; G-142 to G-156; S-143 to S-157; Y-144 to A-158;T-145 to L-159; F-146 to E-160; V-147 to E-161; P-148 to K-162; W-149 toE-163; L-150 to N-164; L-151 to K-165; S-152 to I-166; F-153 to L-167;K-154 to V-168; R-155 to K-169; G-156 to E-170; S-157 to T-171; A-158 toG-172; L-159 to Y-173; E-160 to F-174; E-161 to F-175; K-162 to I-176;E-163 to Y-177; N-164 to G-178; K-165 to Q-179; I-166 to V-180; L-167 toL-181; V-168 to Y-182; K-169 to T-183; E-170 to D-184; T-171 to K-185;G-172 to T-186; Y-173 to Y-187; F-174 to A-188; F-175 to M-189; I-176 toG-190; Y-177 to H-191; G-178 to L-192; Q-179 to I-193; V-180 to Q-194;L-181 to R-195; Y-182 to K-196; T-183 to K-197; D-184 to V-198; K-185 toH-199; T-186 to V-200; Y-187 to F-201; A-188 to G-202; M-189 to D-203;G-190 to E-204; H-191 to L-205; L-192 to S-206; I-193 to L-207; Q-194 toV-208; R-195 to T-209; K-196 to L-210; K-197 to F-211; V-198 to R-212;H-199 to C-213; V-200 to I-214; F-201 to Q-215; G-202 to N-216; D-203 toM-217; E-204 to P-218; L-205 to E-219; S-206 to T-220; L-207 to L-221;V-208 to P-222; T-209 to N-223; L-210 to N-224; F-211 to S-225; R-212 toC-226; C-213 to Y-227; I-214 to S-228; Q-215 to A-229; N-216 to G-230;M-217 to I-231; P-218 to A-232; E-219 to K-233; T-220 to L-234; L-221 toE-235; P-222 to E-236; N-223 to G-237; N-224 to D-238; S-225 to E-239;C-226 to L-240; Y-227 to Q-241; S-228 to L-242; A-229 to A-243; G-230 toI-244; I-231 to P-245; A-232 to R-246; K-233 to E-247; L-234 to N-248;E-235 to A-249; E-236 to Q-250; G-237 to I-251; D-238 to S-252; E-239 toL-253; L-240 to D-254; Q-241 to G-255; L-242 to D-256; A-243 to V-257;I-244 to T-258; P-245 to F-259; R-246 to F-260; E-247 to G-261; N-248 toA-262; A-249 to L-263; Q-250 to K-264; 1-251 to L-265; and S-252 toL-266 of SEQ ID NO:3229. The present invention is also directed toantibodies that bind BLyS polypeptides comprising, or alternatively,consisting of, a contiguous sequence of amino acid residues at least80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the aminoacid sequence of BLyS polypeptides described above.

[0147] In additional embodiments, antibodies of the present inventionmay bind polypeptide fragments comprising, or alternatively consistingof, an amino acid sequence selected from the group consisting ofresidues: M-1 to F-15; D-2 to C-16; E-3 to S-17; S-4 to E-18; A-5 toK-19; K-6 to G-20; T-7 to E-21; L-8 to D-22; P-9 to M-23; P-10 to K-24;P-11 to V-25; C-12 to G-26; L-13 to Y-27; C-14 to D-28; F-15 to P-29;C-16 to I-30; S-17 to T-31; E-18 to P-32; K-19 to Q-33; G-20 to K-34;E-21 to E-35; D-22 to E-36; M-23 to G-37; K-24 to A-38; V-25 to W-39;G-26 to F-40; Y-27 to G-41; D-28 to I-42; P-29 to C-43; I-30 to R-44;T-31 to D-45; P-32 to G-46; Q-33 to R-47; K-34 to L-48; E-35 to L-49;E-36 to A-50; G-37 to A-51; A-38 to T-52; W-39 to L-53; F-40 to L-54;G-41 to L-55; I-42 to A-56; C-43 to L-57; R-44 to L-58; D-45 to S-59;G-46 to S-60; R-47 to S-61; L-48 to F-62; L-49 to T-63; A-50 to A-64;A-51 to M-65; T-52 to S-66; L-53 to L-67; L-54 to Y-68; L-55 to Q-69;A-56 to L-70; L-57 to A-71; L-58 to A-72; S-59 to L-73; S-60 to Q-74;S-61 to A-75; F-62 to D-76; T-63 to L-77; A-64 to M-78; M-65 to N-79;S-66 to L-80; L-67 to R-81; Y-68 to M-82; Q-69 to E-83; L-70 to L-84;A-71 to Q-85; A-72 to S-86; L-73 to Y-87; Q-74 to R-88; A-75 to G-89;D-76 to S-90; L-77 to A-91; M-78 to T-92; N-79 to P-93; L-80 to A-94;R-81 to A-95; M-82 to A-96; E-83 to G-97; L-84 to A-98; Q-85 to P-99;S-86 to E-100; Y-87 to L-101; R-88 to T-102; G-89 to A-103; S-90 toG-104; A-91 to V-105; T-92 to K-106; P-93 to L-107; A-94 to L-108; A-95to T-109; A-96 to P-110; G-97 to A-111; A-98 to A-112; P-99 to P-113;E-100 to R-114; L-101 to P-115; T-102 to H-116; A-103 to N-117; G-104 toS-118; V-105 to S-119; K-106 to R-120; L-107 to G-121; L-108 to H-122;T-109 to R-123; P-10 to N-124; A-111 to R-125; A-112 to R-126; P-113 toA-127; R-114 to F-128; P-115 to Q-129; H-116 to G-130; N-117 to P-131;S-118 to E-132; S-119 to E-133; R-120 to T-134; G-121 to E-135; H-122 toQ-136; R-123 to D-137; N-124 to V-138; R-125 to D-139; R-126 to L-140;A-127 to S-141; F-128 to A-142; Q-129 to P-143; G-130 to P-144; P-131 toA-145; E-132 to P-146; E-133 to C-147; T-134 to L-148; E-135 to P-149;Q-136 to G-150; D-137 to C-151; V-138 to R-152; D-139 to H-153; L-140 toS-154; S-141 to Q-155; A-142 to H-156; P-143 to D-157; P-144 to D-158;A-145 to N-159; P-146 to G-160; C-147 to M-161; L-148 to N-162; P-149 toL-163; G-150 to R-164; C-151 to N-165; R-152 to I-166; H-153 to I-167;S-154 to Q-168; Q-155 to D-169; H-156 to C-170; D-157 to L-171; D-158 toQ-172; N-159 to L-173; G-160 to I-174; M-161 to A-175; N-162 to D-176;L-163 to S-177; R-164 to D-178; N-165 to T-179; 1-166 to P-180; I-167 toA-181; Q-168 to L-182; D-169 to E-183; C-170 to E-184; L-171 to K-185;Q-172 to E-186; L-173 to N-187; I-174 to K-188; A-175 to I-189; D-176 toV-190; S-177 to V-191; D-178 to R-192; T-179 to Q-193; P-180 to T-194;A-181 to G-195; L-182 to Y-196; E-183 to F-197; E-184 to F-198; K-185 toI-199; E-186 to Y-200; N-187 to S-201; K-188 to Q-202; I-189 to V-203;V-190 to L-204; V-191 to Y-205; R-192 to T-206; Q-193 to D-207; T-194 toP-208; G-195 to I-209; Y-196 to F-210; F-197 to A-211; F-198 to M-212;I-199 to G-213; Y-200 to H-214; S-201 to V-215; Q-202 to I-216; V-203 toQ-217; L-204 to R-218; Y-205 to K-219; T-206 to K-220; D-207 to V-221;P-208 to H-222; I-209 to V-223; F-210 to F-224; A-211 to G-225; M-212 toD-226; G-213 to E-227; H-214 to L-228; V-215 to S-229; I-216 to L-230;Q-217 to V-231; R-218 to T-232; K-219 to L-233; K-220 to F-234; V-221 toR-235; H-222 to C-236; V-223 to I-237; F-224 to Q-238; G-225 to N-239;D-226 to M-240; E-227 to P-241; L-228 to K-242; S-229 to T-243; L-230 toL-244; V-231 to P-245; T-232 to N-246; L-233 to N-247; F-234 to S-248;R-235 to C-249; C-236 to Y-250; I-237 to S-251; Q-238 to A-252; N-239 toG-253; M-240 to I-254; P-241 to A-255; K-242 to R-256; T-243 to L-257;L-244 to E-258; P-245 to E-259; N-246 to G-260; N-247 to D-261; S-248 toE-262; C-249 to I-263; Y-250 to Q-264; S-251 to L-265; A-252 to A-266;G-253 to I-267; I-254 to P-268; A-255 to R-269; R-256 to E-270; L-257 toN-271; E-258 to A-272; E-259 to Q-273; G-260 to I-274; D-261 to S-275;E-262 to R-276; I-263 to N-277; Q-264 to G-278; L-265 to D-279; A-266 toD-280; I-267 to T-281; P-268 to F-282; R-269 to F-283; E-270 to G-284;N-271 to A-285; A-272 to L-286; Q-273 to K-287; I-274 to L-288; andS-275 to L-289 of SEQ ID NO:38. The present invention is also directedto antibodies that bind BLyS polypeptides comprising, or alternatively,consisting of, a contiguous sequence of amino acid residues at least80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to the aminoacid sequence of BLyS polypeptides described above.

[0148] It will be recognized by one of ordinary skill in the art thatsome amino acid sequences of the BLyS polypeptides can be varied withoutsignificant effect of the structure or function of the polypeptide. Ifsuch differences in sequence are contemplated, it should be rememberedthat there will be critical areas on the polypeptide which determineactivity.

[0149] Thus, the invention further includes antibodies that bindvariations of BLyS polypeptides which show BLyS polypeptide functionalactivity (e.g., biological activity) or which include regions of BLySpolypeptide such as the polypeptide fragments described herein. Suchmutants include deletions, insertions, inversions, repeats, and typesubstitutions selected according to general rules known in the art so ashave little effect on activity. For example, guidance concerning how tomake phenotypically silent amino acid substitutions is provided inBowie, J. U. et al., “Deciphering the Message in Protein Sequences:Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990),wherein the authors indicate that there are two main approaches forstudying the tolerance of an amino acid sequence to change. The firstmethod relies on the process of evolution, in which mutations are eitheraccepted or rejected by natural selection. The second approach usesgenetic engineering to introduce amino acid changes at specificpositions of a cloned gene and selections or screens to identifysequences that maintain functionality.

[0150] As the authors state, these studies have revealed that proteinsare surprisingly tolerant of amino acid substitutions. The authorsfurther indicate which amino acid changes are likely to be permissive ata certain position of the protein. For example, most buried amino acidresidues require nonpolar side chains, whereas few features of surfaceside chains are generally conserved. Other such phenotypically silentsubstitutions are described in Bowie, J. U. et al., supra, and thereferences cited therein. Typically seen as conservative substitutionsare the replacements, one for another, among the aliphatic amino acidsAla, Val, Leu and Ile; interchange of the hydroxyl residues Ser and Thr,exchange of the acidic residues Asp and Glu, substitution between theamide residues Asn and Gln, exchange of the basic residues Lys and Argand replacements among the aromatic residues Phe, Tyr.

[0151] Thus, antibodies of the present invention may bind fragments,derivatives or analogs of the polypeptide of SEQ ID NO:3228, or thatencoded by the deposited cDNA plasmid, such as (i) polypeptides in whichone or more of the amino acid residues are substituted with a conservedor non-conserved amino acid residue (preferably a conserved amino acidresidue) and such substituted amino acid residue may or may not be oneencoded by the genetic code, or (ii) polypeptides in which one or moreof the amino acid residues includes a substituent group, or (iii)polypeptides in which the extracellular domain of the polypeptide isfused with another compound, such as a compound to increase thehalf-life of the polypeptide (for example, polyethylene glycol), or (iv)polypeptides in which the additional amino acids are fused to theextracellular domain of the polypeptide, such as an IgG Fc fusion regionpeptide or leader or secretory sequence or a sequence which is employedfor purification of the extracellular domain of the polypeptide or aproprotein sequence.

[0152] Antibodies of the present invention may bind fragments,derivatives or analogs of the polypeptide of SEQ ID NO:3229, or thatencoded by the deposited cDNA plasmid, such as (i) polypeptides in whichone or more of the amino acid residues are substituted with a conservedor non-conserved amino acid residue (preferably a conserved amino acidresidue) and such substituted amino acid residue may or may not be oneencoded by the genetic code, or (ii) polypeptides in which one or moreof the amino acid residues includes a substituent group, or (iii)polypeptides in which the extracellular domain of the polypeptide isfused with another compound, such as a compound to increase thehalf-life of the polypeptide (for example, polyethylene glycol), or (iv)polypeptides in which the additional amino acids are fused to theextracellular domain of the polypeptide, such as, a soluble biologicallyactive fragment of another TNF ligand family member (e.g., CD40 Ligand),an IgG Fc fusion region peptide or leader or secretory sequence or asequence which is employed for purification of the extracellular domainof the polypeptide or a proprotein sequence. Such fragments, derivativesand analogs are deemed to be within the scope of those skilled in theart from the teachings herein.

[0153] Thus, the antibodies of the invention may bind BLyS polypeptidesthat include one or more amino acid substitutions, deletions oradditions, either from natural mutations or human manipulation. Asindicated, changes are preferably of a minor nature, such asconservative amino acid substitutions that do not significantly affectthe folding or activity of the protein (see Table 13). TABLE 13Conservative Amino Acid Substitutions. Aromatic Phenylalanine TryptophanTyrosine Hydrophobic Leucine Isoleucine Valine Polar GlutamineAsparagine Basic Arginine Lysine Histidine Acidic Aspartic Acid GlutamicAcid Small Alanine Serine Threonine Methionine Glycine

[0154] In one embodiment of the invention, antibodies of the presentinvention bind polypeptides comprising, or alternatively consisting of,the amino acid sequence of a BLyS polypeptide having an amino acidsequence which contains at least one conservative amino acidsubstitution, but not more than 50 conservative amino acidsubstitutions, even more preferably, not more than 40 conservative aminoacid substitutions, still more preferably, not more than 30 conservativeamino acid substitutions, and still even more preferably, not more than20 conservative amino acid substitutions. In one embodiment of theinvention, antibodies of the present invention bind polypeptidescomprising, or alternatively consisting of, the amino acid sequence of aBLyS polypeptide having an amino acid sequence which contains at leastone conservative amino acid substitution, but not more than 10, 9, 8, 7,6, 5, 4, 3, 2 or 1 conservative amino acid substitutions.

[0155] For example, site directed changes at the amino acid level ofBLyS can be made by replacing a particular amino acid with aconservative substitution. Antibodies of the present invention may bindBLyS amino acid sequences containing conservative substitution mutationsof the polypeptide of SEQ ID NO:3228 including: M1 replaced with A, G,I, L, S, T, or V; D2 replaced with E; D3 replaced with E; S4 replacedwith A, G, I, L, T, M, or V; T5 replaced with A, G, I, L, S, M, or V; E6replaced with D; R7 replaced with H, or K; E8 replaced with D; Q9replaced with N; S10 replaced with A, G, I, L, T, M, or V; R11 replacedwith H, or K; L12 replaced with A, G, I, S, T, M, or V; T13 replacedwith A, G, I, L, S, M, or V; S14 replaced with A, G, I, L, T, M, or V;L16 replaced with A, G, I, S, T, M, or V; K17 replaced with H, or R; K18replaced with H, or R; R19 replaced with H, or K; E20 replaced with D;E21 replaced with D; M22 replaced with A, G, I, L, S, T, or V; K23replaced with H, or R; L24 replaced with A, G, I, S, T, M, or V; K25replaced with H, or R; E26 replaced with D; V28 replaced with A, G, I,L, S, T, or M; S29 replaced with A, G, I, L, T, M, or V; I30 replacedwith A, G, L, S, T, M, or V; L31 replaced with A, G, I, S, T, M, or V;R33 replaced with H, or K; K34 replaced with H, or R; E35 replaced withD; S36 replaced with A, G, I, L, T, M, or V; S38 replaced with A, G, I,L, T, M, or V; V39 replaced with A, G, I, L, S, T, or M; R40 replacedwith H, or K; S41 replaced with A, G, I, L, T, M, or V; S42 replacedwith A, G, I, L, T, M, or V; K43 replaced with H, or R; D44 replacedwith E; G45 replaced with A, I, L, S, T, M, or V; K46 replaced with H,or R; L47 replaced with A, G, I, S, T, M, or V; L48 replaced with A, G,I, S, T, M, or V; A49 replaced with G, I, L, S, T, M, or V; A50 replacedwith G, I, L, S, T, M, or V; T51 replaced with A, G, I, L, S, M, or V;L52 replaced with A, G, I, S, T, M, or V; L53 replaced with A, G, I, S,T, M, or V; L54 replaced with A, G, I, S, T, M, or V; A55 replaced withG, I, L, S, T, M, or V; L56 replaced with A, G, I, S, T, M, or V; L57replaced with A, G, I, S, T, M, or V; S58 replaced with A, G, I, L, T,M, or V; L61 replaced with A, G, I, S, T, M, or V; T62 replaced with A,G, I, L, S, M, or V; V63 replaced with A, G, I, L, S, T, or M; V64replaced with A, G, I, L, S, T, or M; S65 replaced with A, G, I, L, T,M, or V; F66 replaced with W, or Y; Y67 replaced with F, or W; Q68replaced with N; V69 replaced with A, G, I, L, S, T, or M; A70 replacedwith G, I, L, S, T, M, or V; A71 replaced with G, I, L, S, T, M, or V;L72 replaced with A, G, I, S, T, M, or V; Q73 replaced with N; G74replaced with A, I, L, S, T, M, or V; D75 replaced with E; L76 replacedwith A, G, I, S, T, M, or V; A77 replaced with G, I, L, S, T, M, or V;S78 replaced with A, G, I, L, T, M, or V; L79 replaced with A, G, I, S,T, M, or V; R80 replaced with H, or K; A81 replaced with G, I, L, S, T,M, or V; E82 replaced with D; L83 replaced with A, G, I, S, T, M, or V;Q84 replaced with N; G85 replaced with A, I, L, S, T, M, or V; H86replaced with K, or R; H87 replaced with K, or R; A88 replaced with G,I, L, S, T, M, or V; E89 replaced with D; K90 replaced with H, or R; L91replaced with A, G, I, S, T, M, or V; A93 replaced with G, I, L, S, T,M, or V; G94 replaced with A, I, L, S, T, M, or V; A95 replaced with G,I, L, S, T, M, or V; G96 replaced with A, I, L, S, T, M, or V; A97replaced with G, I, L, S, T, M, or V; K99 replaced with H, or R; A100replaced with G, I, L, S, T, M, or V; G101 replaced with A, I, L, S, T,M, or V; L102 replaced with A, G, I, S, T, M, or V; E103 replaced withD; E104 replaced with D; A105 replaced with G, I, L, S, T, M, or V; A107replaced with G, I, L, S, T, M, or V; V108 replaced with A, G, I, L, S,T, or M; T109 replaced with A, G, I, L, S, M, or V; A110 replaced withG, I, L, S, T, M, or V; G111 replaced with A, I, L, S, T, M, or V; L112replaced with A, G, I, S, T, M, or V; K113 replaced with H, or R; I114replaced with A, G, L, S, T, M, or V; F115 replaced with W, or Y; E116replaced with D; A119 replaced with G, I, L, S, T, M, or V; G121replaced with A, I, L, S, T, M, or V; E122 replaced with D; G123replaced with A, I, L, S, T, M, or V; N124 replaced with Q; S125replaced with A, G, I, L, T, M, or V; S126 replaced with A, G, I, L, T,M, or V; Q127 replaced with N; N128 replaced with Q; S129 replaced withA, G, I, L, T, M, or V; R130 replaced with H, or K; N131 replaced withQ; K132 replaced with H, or R; R133 replaced with H, or K; A134 replacedwith G, I, L, S, T, M, or V; V135 replaced with A, G, I, L, S, T, or M;Q136 replaced with N; G137 replaced with A, I, L, S, T, M, or V; E139replaced with D; E140 replaced with D; T141 replaced with A, G, I, L, S,M, or V; V142 replaced with A, G, I, L, S, T, or M; T143 replaced withA, G, I, L, S, M, or V; Q144 replaced with N; D145 replaced with E; L147replaced with A, G, I, S, T, M, or V; Q148 replaced with N; L149replaced with A, G, I, S, T, M, or V; I150 replaced with A, G, L, S, T,M, or V; A151 replaced with G, I, L, S, T, M, or V; D152 replaced withE; S153 replaced with A, G, I, L, T, M, or V; E154 replaced with D; T155replaced with A, G, I, L, S, M, or V; T157 replaced with A, G, I, L, S,M, or V; I158 replaced with A, G, L, S, T, M, or V; Q159 replaced withN; K160 replaced with H, or R; G161 replaced with A, I, L, S, T, M, orV; S162 replaced with A, G, I, L, T, M, or V; Y163 replaced with F, orW; T164 replaced with A, G, I, L, S, M, or V; F165 replaced with W, orY; V166 replaced with A, G, I, L, S, T, or M; W168 replaced with F, orY; L169 replaced with A, G, I, S, T, M, or V; L170 replaced with A, G,I, S, T, M, or V; S171 replaced with A, G, I, L, T, M, or V; F172replaced with W, or Y; K173 replaced with H, or R; R174 replaced with H,or K; G175 replaced with A, I, L, S, T, M, or V; S176 replaced with A,G, I, L, T, M, or V; A177 replaced with G, I, L, S, T, M, or V; L178replaced with A, G, I, S, T, M, or V; E179 replaced with D; E180replaced with D; K181 replaced with H, or R; E182 replaced with D; N183replaced with Q; K184 replaced with H, or R; I185 replaced with A, G, L,S, T, M, or V; L186 replaced with A, G, I, S, T, M, or V; V187 replacedwith A, G, I, L, S, T, or M; K188 replaced with H, or R; E189 replacedwith D; T190 replaced with A, G, I, L, S, M, or V; G191 replaced with A,I, L, S, T, M, or V; Y192 replaced with F, or W; F193 replaced with W,or Y; F194 replaced with W, or Y; I195 replaced with A, G, L, S, T, M,or V; Y196 replaced with F, or W; G197 replaced with A, I, L, S, T, M,or V; Q198 replaced with N; V199 replaced with A, G, I, L, S, T, or M;L200 replaced with A, G, I, S, T, M, or V; Y201 replaced with F, or W;T202 replaced with A, G, I, L, S, M, or V; D203 replaced with E; K204replaced with H, or R; T205 replaced with A, G, I, L, S, M, or V; Y206replaced with F, or W; A207 replaced with G, I, L, S, T, M, or V; M208replaced with A, G, I, L, S, T, or V; G209 replaced with A, I, L, S, T,M, or V; H210 replaced with K, or R; L211 replaced with A, G, I, S, T,M, or V; I212 replaced with A, G, L, S, T, M, or V; Q213 replaced withN; R214 replaced with H, or K; K215 replaced with H, or R; K216 replacedwith H, or R; V217 replaced with A, G, I, L, S, T, or M; H218 replacedwith K, or R; V219 replaced with A, G, I, L, S, T, or M; F220 replacedwith W, or Y; G221 replaced with A, I, L, S, T, M, or V; D222 replacedwith E; E223 replaced with D; L224 replaced with A, G, I, S, T, M, or V;S225 replaced with A, G, I, L, T, M, or V; L226 replaced with A, G, I,S, T, M, or V; V227 replaced with A, G, I, L, S, T, or M; T228 replacedwith A, G, I, L, S, M, or V; L229 replaced with A, G, I, S, T, M, or V;F230 replaced with W, or Y; R231 replaced with H, or K; I233 replacedwith A, G, L, S, T, M, or V; Q234 replaced with N; N235 replaced with Q;M236 replaced with A, G, I, L, S, T, or V; E238 replaced with D; T239replaced with A, G, I, L, S, M, or V; L240 replaced with A, G, I, S, T,M, or V; N242 replaced with Q; N243 replaced with Q; S244 replaced withA, G, I, L, T, M, or V; Y246 replaced with F, or W; S247 replaced withA, G, I, L, T, M, or V; A248 replaced with G, I, L, S, T, M, or V; G249replaced with A, I, L, S, T, M, or V; I250 replaced with A, G, L, S, T,M, or V; A251 replaced with G, I, L, S, T, M, or V; K252 replaced withH, or R; L253 replaced with A, G, I, S, T, M, or V; E254 replaced withD; E255 replaced with D; G256 replaced with A, I, L, S, T, M, or V; D257replaced with E; E258 replaced with D; L259 replaced with A, G, I, S, T,M, or V; Q260 replaced with N; L261 replaced with A, G, I, S, T, M, orV; A262 replaced with G, I, L, S, T, M, or V; I263 replaced with A, G,L, S, T, M, or V; R265 replaced with H, or K; E266 replaced with D; N267replaced with Q; A268 replaced with G, I, L, S, T, M, or V; Q269replaced with N; I270 replaced with A, G, L, S, T, M, or V; S271replaced with A, G, I, L, T, M, or V; L272 replaced with A, G, I, S, T,M, or V; D273 replaced with E; G274 replaced with A, I, L, S, T, M, orV; D275 replaced with E; V276 replaced with A, G, I, L, S, T, or M; T277replaced with A, G, I, L, S, M, or V; F278 replaced with W, or Y; F279replaced with W, or Y; G280 replaced with A, I, L, S, T, M, or V; A281replaced with G, I, L, S, T, M, or V; L282 replaced with A, G, I, S, T,M, or V; K283 replaced with H, or R; L284 replaced with A, G, I, S, T,M, or V; and/or L285 replaced with A, G, I, S, T, M, or V.

[0156] In another embodiment, site directed changes at the amino acidlevel of BLyS can be made by replacing a particular amino acid with aconservative substitution. Antibodies of the present invention may bindBLyS amino acid sequences containing conservative substitution mutationsof the polypeptide of SEQ ID NO:3229 including: M1 replaced with A, G,I, L, S, T, or V; D2 replaced with E; D3 replaced with E; S4 replacedwith A, G, I, L, T, M, or V; T5 replaced with A, G, I, L, S, M, or V; E6replaced with D; R7 replaced with H, or K; E8 replaced with D; Q9replaced with N; S10 replaced with A, G, I, L, T, M, or V; R11 replacedwith H, or K; L12 replaced with A, G, I, S, T, M, or V; T13 replacedwith A, G, I, L, S, M, or V; S14 replaced with A, G, I, L, T, M, or V;L16 replaced with A, G, I, S, T, M, or V; K17 replaced with H, or R; K18replaced with H, or R; R19 replaced with H, or K; E20 replaced with D;E21 replaced with D; M22 replaced with A, G, I, L, S, T, or V; K23replaced with H, or R; L24 replaced with A, G, I, S, T, M, or V; K25replaced with H, or R; E26 replaced with D; V28 replaced with A, G, I,L, S, T, or M; S29 replaced with A, G, I, L, T, M, or V; 130 replacedwith A, G, L, S, T, M, or V; L31 replaced with A, G, I, S, T, M, or V;R33 replaced with H, or K; K34 replaced with H, or R; E35 replaced withD; S36 replaced with A, G, I, L, T, M, or V; S38 replaced with A, G, I,L, T, M, or V; V39 replaced with A, G, I, L, S, T, or M; R40 replacedwith H, or K; S41 replaced with A, G, I, L, T, M, or V; S42 replacedwith A, G, I, L, T, M, or V; K43 replaced with H, or R; D44 replacedwith E; G45 replaced with A, I, L, S, T, M, or V; K46 replaced with H,or R; L47 replaced with A, G, I, S, T, M, or V; L48 replaced with A, G,I, S, T, M, or V; A49 replaced with G, I, L, S, T, M, or V; A50 replacedwith G, I, L, S, T, M, or V; T51 replaced with A, G, I, L, S, M, or V;L52 replaced with A, G, I, S, T, M, or V; L53 replaced with A, G, I, S,T, M, or V; L54 replaced with A, G, I, S, T, M, or V; A55 replaced withG, I, L, S, T, M, or V; L56 replaced with A, G, I, S, T, M, or V; L57replaced with A, G, I, S, T, M, or V; S58 replaced with A, G, I, L, T,M, or V; L61 replaced with A, G, I, S, T, M, or V; T62 replaced with A,G, I, L, S, M, or V; V63 replaced with A, G, I, L, S, T, or M; V64replaced with A, G, I, L, S, T, or M; S65 replaced with A, G, I, L, T,M, or V; F66 replaced with W, or Y; Y67 replaced with F, or W; Q68replaced with N; V69 replaced with A, G, I, L, S, T, or M; A70 replacedwith G, I, L, S, T, M, or V; A71 replaced with G, I, L, S, T, M, or V;L72 replaced with A, G, I, S, T, M, or V; Q73 replaced with N; G74replaced with A, I, L, S, T, M, or V; D75 replaced with E; L76 replacedwith A, G, I, S, T, M, or V; A77 replaced with G, I, L, S, T, M, or V;S78 replaced with A, G, I, L, T, M, or V; L79 replaced with A, G, I, S,T, M, or V; R80 replaced with H, or K; A81 replaced with G, I, L, S, T,M, or V; E82 replaced with D; L83 replaced with A, G, I, S, T, M, or V;Q84 replaced with N; G85 replaced with A, I, L, S, T, M, or V; H86replaced with K, or R; H87 replaced with K, or R; A88 replaced with G,I, L, S, T, M, or V; E89 replaced with D; K90 replaced with H, or R; L91replaced with A, G, I, S, T, M, or V; A93 replaced with G, I, L, S, T,M, or V; G94 replaced with A, I, L, S, T, M, or V; A95 replaced with G,I, L, S, T, M, or V; G96 replaced with A, I, L, S, T, M, or V; A97replaced with G, I, L, S, T, M, or V; K99 replaced with H, or R; A100replaced with G, I, L, S, T, M, or V; G101 replaced with A, I, L, S, T,M, or V; L102 replaced with A, G, I, S, T, M, or V; E103 replaced withD; E104 replaced with D; A105 replaced with G, I, L, S, T, M, or V; A107replaced with G, I, L, S, T, M, or V; V108 replaced with A, G, I, L, S,T, or M; T109 replaced with A, G, I, L, S, M, or V; A110 replaced withG, I, L, S, T, M, or V; G111 replaced with A, I, L, S, T, M, or V; L112replaced with A, G, I, S, T, M, or V; K113 replaced with H, or R; I114replaced with A, G, L, S, T, M, or V; F115 replaced with W, or Y; E116replaced with D; A119 replaced with G, I, L, S, T, M, or V; G121replaced with A, I, L, S, T, M, or V; E122 replaced with D; G123replaced with A, I, L, S, T, M, or V; N124 replaced with Q; S125replaced with A, G, I, L, T, M, or V; S126 replaced with A, G, I, L, T,M, or V; Q127 replaced with N; N128 replaced with Q; S129 replaced withA, G, I, L, T, M, or V; R130 replaced with H, or K; N131 replaced withQ; K132 replaced with H, or R; R133 replaced with H, or K; A134 replacedwith G, I, L, S, T, M, or V; V135 replaced with A, G, I, L, S, T, or M;Q136 replaced with N; G137 replaced with A, I, L, S, T, M, or V; E139replaced with D; E140 replaced with D; T141 replaced with A, G, I, L, S,M, or V; G142 replaced with A, I, L, S, T, M, or V; S143 replaced withA, G, I, L, T, M, or V; Y144 replaced with F, or W; T145 replaced withA, G, I, L, S, M, or V; F146 replaced with W, or Y; V147 replaced withA, G, I, L, S, T, or M; W149 replaced with F, or Y; L150 replaced withA, G, I, S, T, M, or V; L151 replaced with A, G, I, S, T, M, or V; S152replaced with A, G, I, L, T, M, or V; F153 replaced with W, or Y; K154replaced with H, or R; R155 replaced with H, or K; G156 replaced with A,I, L, S, T, M, or V; S157 replaced with A, G, I, L, T, M, or V; A158replaced with G, I, L, S, T, M, or V; L159 replaced with A, G, I, S, T,M, or V; E160 replaced with D; E161 replaced with D; K162 replaced withH, or R; E163 replaced with D; N164 replaced with Q; K165 replaced withH, or R; I166 replaced with A, G, L, S, T, M, or V; L167 replaced withA, G, I, S, T, M, or V; V168 replaced with A, G, I, L, S, T, or M; K169replaced with H, or R; E170 replaced with D; T171 replaced with A, G, I,L, S, M, or V; G172 replaced with A, I, L, S, T, M, or V; Y173 replacedwith F, or W; F174 replaced with W, or Y; F175 replaced with W, or Y;I176 replaced with A, G, L, S, T, M, or V; Y177 replaced with F, or W;G178 replaced with A, I, L, S, T, M, or V; Q179 replaced with N; V180replaced with A, G, I, L, S, T, or M; L181 replaced with A, G, I, S, T,M, or V; Y182 replaced with F, or W; T183 replaced with A, G, I, L, S,M, or V; D184 replaced with E; K185 replaced with H, or R; T186 replacedwith A, G, I, L, S, M, or V; Y187 replaced with F, or W; A188 replacedwith G, I, L, S, T, M, or V; M189 replaced with A, G, I, L, S, T, or V;G190 replaced with A, I, L, S, T, M, or V; H191 replaced with K, or R;L192 replaced with A, G, I, S, T, M, or V; I193 replaced with A, G, L,S, T, M, or V; Q194 replaced with N; R195 replaced with H, or K; K196replaced with H, or R; K197 replaced with H, or R; V198 replaced with A,G, I, L, S, T, or M; H199 replaced with K, or R; V200 replaced with A,G, I, L, S, T, or M; F201 replaced with W, or Y; G202 replaced with A,I, L, S, T, M, or V; D203 replaced with E; E204 replaced with D; L205replaced with A, G, I, S, T, M, or V; S206 replaced with A, G, I, L, T,M, or V; L207 replaced with A, G, I, S, T, M, or V; V208 replaced withA, G, I, L, S, T, or M; T209 replaced with A, G, I, L, S, M, or V; L210replaced with A, G, I, S, T, M, or V; F211 replaced with W, or Y; R212replaced with H, or K; I214 replaced with A, G, L, S, T, M, or V; Q215replaced with N; N216 replaced with Q; M217 replaced with A, G, I, L, S,T, or V; E219 replaced with D; T220 replaced with A, G, I, L, S, M, orV; L221 replaced with A, G, I, S, T, M, or V; N223 replaced with Q; N224replaced with Q; S225 replaced with A, G, I, L, T, M, or V; Y227replaced with F, or W; S228 replaced with A, G, I, L, T, M, or V; A129replaced with G, I, L, S, T, M, or V; G230 replaced with A, I, L, S, T,M, or V; I231 replaced with A, G, L, S, T, M, or V; A232 replaced withG, I, L, S, T, M, or V; K233 replaced with H, or R; L234 replaced withA, G, I, S, T, M, or V; E235 replaced with D; E236 replaced with D; G237replaced with A, I, L, S, T, M, or V; D238 replaced with E; E239replaced with D; L240 replaced with A, G, I, S, T, M, or V; Q241replaced with N; L242 replaced with A, G, I, S, T, M, or V; A243replaced with G, I, L, S, T, M, or V; I244 replaced with A, G, L, S, T,M, or V; R246 replaced with H, or K; E247 replaced with D; N248 replacedwith Q; A249 replaced with G, I, L, S, T, M, or V; Q250 replaced with N;I251 replaced with A, G, L, S, T, M, or V; S252 replaced with A, G, I,L, T, M, or V; L253 replaced with A, G, I, S, T, M, or V; D254 replacedwith E; G255 replaced with A, I, L, S, T, M, or V; D256 replaced with E;V257 replaced with A, G, I, L, S, T, or M; T258 replaced with A, G, I,L, S, M, or V; F259 replaced with W, or Y; F260 replaced with W, or Y;G261 replaced with A, I, L, S, T, M, or V; A262 replaced with G, I, L,S, T, M, or V; L263 replaced with A, G, I, S, T, M, or V; K264 replacedwith H, or R; L265 replaced with A, G, I, S, T, M, or V; and/or L266replaced with A, G, I, S, T, M, or V.

[0157] In another embodiment, site directed changes at the amino acidlevel of BLyS can be made by replacing a particular amino acid with aconservative substitution. Antibodies of the present invention may bindBLyS amino acid sequences containing conservative substitution mutationsof the polypeptide of any one of SEQ ID NOS:3230-3237.

[0158] Amino acids in the BLyS polypeptides that are essential forfunction can be identified by methods known in the art, such assite-directed mutagenesis or alanine-scanning mutagenesis (Cunninghamand Wells, Science 244:1081-1085 (1989)). The latter procedureintroduces single alanine mutations at every residue in the molecule.The resulting mutant molecules are then tested for functional activity,such ligand binding and the ability to stimulate lymphocyte (e.g., Bcell) as, for example, proliferation, differentiation, and/oractivation. Accordingly, antibodies of the present invention may bindamino acids in the BLyS polypeptides that are essential for function. Inpreferred embodiments, antibodies of the present invention bind aminoacids in the BLyS polypeptides that are essential for function andinhibit BLyS polypeptide function. In other preferred embodiments,antibodies of the present invention bind amino acids in the BLySpolypeptides that are essential for function and enhance BLySpolypeptide function.

[0159] Of special interest are substitutions of charged amino acids withother charged or neutral amino acids which may produce proteins withhighly desirable improved characteristics, such as less aggregation.Aggregation may not only reduce activity but also be problematic whenpreparing pharmaceutical formulations, because aggregates can beimmunogenic (Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967);Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev.Therapeutic Drug Carrier Systems 10:307-377 (1993).

[0160] In another embodiment, the invention provides for antibodies thatbind polypeptides having amino acid sequences containingnon-conservative substitutions of the amino acid sequence provided inSEQ ID NO:3228. For example, non-conservative substitutions of the BLySprotein sequence provided in SEQ ID NO:3228 include: M1 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C; D2 replaced with H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, P, or C; D3 replaced with H, K, R, A, G,I, L, S, T, M, V, N, Q, F, W, Y, P, or C; S4 replaced with D, E, H, K,R, N, Q, F, W, Y, P, or C; T5 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; E6 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, P, or C; R7 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F,W, Y, P, or C; E8 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; Q9 replaced with D, E, H, K, R, A, G, I, L, S, T, M,V, F, W, Y, P, or C; S10 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; R11 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; L12 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; T13replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S14 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; C15 replaced with D, E, H, K, R,A, G, I, L, S, T, M, V, N, Q, F, W, Y, or P; L16 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; K17 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; K18 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; R19 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; E20 replaced with H, K, R, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; E21 replaced with H, K, R, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; M22 replaced with D, E, H, K, R, N,Q, F, W, Y, P, or C; K23 replaced with D, E, A, G, I, L, S, T, M, V, N,Q, F, W, Y, P, or C; L24 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; K25 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; E26 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; C27 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, or P; V28 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;S29 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; I30 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; L31 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; P32 replaced with D, E, H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, or C; R33 replaced with D, E, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; K34 replaced with D, E, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; E35 replaced with H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, P, or C; S36 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; P37 replaced with D, E, H, K, R, A, G, I, L, S,T, M, V, N, Q, F, W, Y, or C; S38 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; V39 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;R40 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;S41 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S42 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; K43 replaced with D, E, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; D44 replaced with H, K, R,A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; G45 replaced with D, E,H, K, R, N, Q, F, W, Y, P, or C; K46 replaced with D, E, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; L47 replaced with D, E, H, K, R, N, Q,F, W, Y, P, or C; L48 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC; A49 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A50 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; T51 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; L52 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; L53 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;L54 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A55 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; L56 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; L57 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; S58 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;C59 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y,or P; C60 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, or P; L61 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; T62replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; V63 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; V64 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; S65 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; F66 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V,P, or C; Y67 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V,P, or C; Q68 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W,Y, P, or C; V69 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A70replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A71 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; L72 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; Q73 replaced with D, E, H, K, R, A, G, I, L, S,T, M, V, F, W, Y, P, or C; G74 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; D75 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, P, or C; L76 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;A77 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S78 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; L79 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; R80 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; A81 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; E82 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; L83 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC; Q84 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P,or C; G85 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; H86replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; H87replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; A88replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; E89 replaced withH, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; K90 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; L91 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; P92 replaced with D, E, H,K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; A93 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C; G94 replaced with D, E, H, K, R, N,Q, F, W, Y, P, or C; A95 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; G96 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A97replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P98 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; K99 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; A100 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; G101 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; L102 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; E103 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; E104 replaced with H, K, R, A, G, I, L, S, T, M, V, N,Q, F, W, Y, P, or C; A105 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; P106 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, or C; A107 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;V108 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; T109 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; A110 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; G111 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; L112 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;K113 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;I114 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; F115 replacedwith D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; E116 replacedwith H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; P117replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orC; P118 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W,Y, or C; A119 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P120replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orC; G121 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; E122replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;G123 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; N124 replacedwith D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; S125replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S126 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; Q127 replaced with D, E, H, K, R,A, G, I, L, S, T, M, V, F, W, Y, P, or C; N128 replaced with D, E, H, K,R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; S129 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; R130 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; N131 replaced with D, E, H, K, R, A, G, I,L, S, T, M, V, F, W, Y, P, or C; K132 replaced with D, E, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; R133 replaced with D, E, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; A134 replaced with D, E, H, K, R, N, Q,F, W, Y, P, or C; V135 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC; Q136 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P,or C; G137 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P138replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orC; E139 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; E140 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; T141 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; V142replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; T143 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; Q144 replaced with D, E, H, K, R,A, G, I, L, S, T, M, V, F, W, Y, P, or C; D145 replaced with H, K, R, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; C146 replaced with D, E, H,K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or P; L147 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C; Q148 replaced with D, E, H, K, R, A,G, I, L, S, T, M, V, F, W, Y, P, or C; L149 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; I150 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; A151 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; D152replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;S153 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; E154 replacedwith H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; T155replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P156 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; T157replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; I158 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; Q159 replaced with D, E, H, K, R,A, G, I, L, S, T, M, V, F, W, Y, P, or C; K160 replaced with D, E, A, G,I, L, S, T, M, V, N, Q, F, W, Y, P, or C; G161 replaced with D, E, H, K,R, N, Q, F, W, Y, P, or C; S162 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; Y163 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M,V, P, or C; T164 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;F165 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C;V166 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P167 replacedwith D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; W168replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; L169replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L170 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; S171 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; F172 replaced with D, E, H, K, R, N, Q, A, G, I,L, S, T, M, V, P, or C; K173 replaced with D, E, A, G, I, L, S, T, M, V,N, Q, F, W, Y, P, or C; R174 replaced with D, E, A, G, I, L, S, T, M, V,N, Q, F, W, Y, P, or C; G175 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; S176 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A177replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L178 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; E179 replaced with H, K, R, A, G,I, L, S, T, M, V, N, Q, F, W, Y, P, or C; E180 replaced with H, K, R, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; K181 replaced with D, E, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; E182 replaced with H, K, R,A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; N183 replaced with D, E,H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; K184 replaced with D,E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; I185 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C; L186 replaced with D, E, H, K, R, N,Q, F, W, Y, P, or C; V187 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; K188 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; E189 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; T190 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; G191replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; Y192 replaced withD, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; F193 replaced withD, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; F194 replaced withD, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; I195 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; Y196 replaced with D, E, H, K, R,N, Q, A, G, I, L, S, T, M, V, P, or C; G197 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; Q198 replaced with D, E, H, K, R, A, G, I, L, S,T, M, V, F, W, Y, P, or C; V199 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; L200 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;Y201 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C;T202 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; D203 replacedwith H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; K204replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; T205replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; Y206 replaced withD, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; A207 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; M208 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; G209 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; H210 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; L211 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; I212replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; Q213 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; R214 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; K215 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; K216 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; V217 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; H218 replaced with D, E, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; V219 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; F220 replaced with D, E, H, K, R, N, Q, A,G, I, L, S, T, M, V, P, or C; G221 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; D222 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; E223 replaced with H, K, R, A, G, I, L, S, T, M, V, N,Q, F, W, Y, P, or C; L224 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; S225 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L226replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; V227 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; T228 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; L229 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; F230 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V,P, or C; R231 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; C232 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, or P; I233 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;Q234 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, orC; N235 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P,or C; M236 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P237replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orC; E238 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; T239 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L240replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P241 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; N242replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C;N243 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, orC; S244 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; C245replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orP; Y246 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, orC; S247 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A248replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; G249 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; I250 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; A251 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; K252 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; L253 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; E254replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;E255 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, orC; G256 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; D257replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;E258 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, orC; L259 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; Q260replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C;L261 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A262 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; I263 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; P264 replaced with D, E, H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, or C; R265 replaced with D, E, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; E266 replaced with H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, P, or C; N267 replaced with D, E, H, K, R,A, G, I, L, S, T, M, V, F, W, Y, P, or C; A268 replaced with D, E, H, K,R, N, Q, F, W, Y, P, or C; Q269 replaced with D, E, H, K, R, A, G, I, L,S, T, M, V, F, W, Y, P, or C; I270 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; S271 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;L272 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; D273 replacedwith H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; G274replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; D275 replaced withH, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; V276 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; T277 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; F278 replaced with D, E, H, K, R, N, Q, A,G, I, L, S, T, M, V, P, or C; F279 replaced with D, E, H, K, R, N, Q, A,G, I, L, S, T, M, V, P, or C; G280 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; A281 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;L282 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; K283 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; L284 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; and/or L285 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C.

[0161] In an additional embodiment, antibodies of the present inventionbind BLyS polypeptides comprising, or alternatively consisting of, aBLyS amino acid sequence in which more than one amino acid (e.g., 2, 3,4, 5, 6, 7, 8, 9, 10, 15, 20, 30 and 50) is replaced with thesubstituted amino acids as described above (either conservative ornonconservative).

[0162] In another embodiment of the invention, antibodies of the presentinvention bind BLyS polypeptides with non-conservative substitutions ofthe sequence provided in SEQ ID NO:3229 including: M1 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C; D2 replaced with H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, P, or C; D3 replaced with H, K, R, A, G,I, L, S, T, M, V, N, Q, F, W, Y, P, or C; S4 replaced with D, E, H, K,R, N, Q, F, W, Y, P, or C; T5 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; E6 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, P, or C; R7 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F,W, Y, P, or C; E8 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; Q9 replaced with D, E, H, K, R, A, G, I, L, S, T, M,V, F, W, Y, P, or C; S10 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; R11 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; L12 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; T13replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S14 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; C15 replaced with D, E, H, K, R,A, G, I, L, S, T, M, V, N, Q, F, W, Y, or P; L16 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; K17 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; K18 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; R19 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; E20 replaced with H, K, R, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; E21 replaced with H, K, R, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; M22 replaced with D, E, H, K, R, N,Q, F, W, Y, P, or C; K23 replaced with D, E, A, G, I, L, S, T, M, V, N,Q, F, W, Y, P, or C; L24 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; K25 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; E26 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; C27 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, or P; V28 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;S29 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; I30 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; L31 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; P32 replaced with D, E, H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, or C; R33 replaced with D, E, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; K34 replaced with D, E, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; E35 replaced with H, K, R, A, G, I,L, S, T, M, V, N, Q, F, W, Y, P, or C; S36 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; P37 replaced with D, E, H, K, R, A, G, I, L, S,T, M, V, N, Q, F, W, Y, or C; S38 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; V39 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;R40 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;S41 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S42 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; K43 replaced with D, E, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; D44 replaced with H, K, R,A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; G45 replaced with D, E,H, K, R, N, Q, F, W, Y, P, or C; K46 replaced with D, E, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; L47 replaced with D, E, H, K, R, N, Q,F, W, Y, P, or C; L48 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC; A49 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A50 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; T51 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; L52 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; L53 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;L54 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A55 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; L56 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; L57 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; S58 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;C59 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y,or P; C60 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, or P; L61 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; T62replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; V63 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; V64 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; S65 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; F66 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V,P, or C; Y67 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V,P, or C; Q68 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W,Y, P, or C; V69 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A70replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A71 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; L72 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; Q73 replaced with D, E, H, K, R, A, G, I, L, S,T, M, V, F, W, Y, P, or C; G74 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; D75 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, P, or C; L76 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;A77 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S78 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; L79 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; R80 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; A81 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; E82 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; L83 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC; Q84 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P,or C; G85 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; H86replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; H87replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; A88replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; E89 replaced withH, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; K90 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; L91 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; P92 replaced with D, E, H,K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; A93 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C; G94 replaced with D, E, H, K, R, N,Q, F, W, Y, P, or C; A95 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; G96 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A97replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P98 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; K99 replacedwith D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; A100 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; G101 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; L102 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; E103 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; E104 replaced with H, K, R, A, G, I, L, S, T, M, V, N,Q, F, W, Y, P, or C; A105 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; P106 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F,W, Y, or C; A107 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;V108 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; T109 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; A110 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; G111 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; L112 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C;K113 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;I114 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; F115 replacedwith D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; E116 replacedwith H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; P117replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orC; P118 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W,Y, or C; A119 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P120replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orC; G121 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; E122replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;G123 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; N124 replacedwith D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; S125replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S126 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; Q127 replaced with D, E, H, K, R,A, G, I, L, S, T, M, V, F, W, Y, P, or C; N128 replaced with D, E, H, K,R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; S129 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; R130 replaced with D, E, A, G, I, L, S, T,M, V, N, Q, F, W, Y, P, or C; N131 replaced with D, E, H, K, R, A, G, I,L, S, T, M, V, F, W, Y, P, or C; K132 replaced with D, E, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; R133 replaced with D, E, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; A134 replaced with D, E, H, K, R, N, Q,F, W, Y, P, or C; V135 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC; Q136 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P,or C; G137 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P138replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, orC; E139 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; E140 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y,P, or C; T141 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; G142replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S143 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; Y144 replaced with D, E, H, K, R,N, Q, A, G, I, L, S, T, M, V, P, or C; T145 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; F146 replaced with D, E, H, K, R, N, Q, A, G, I,L, S, T, M, V, P, or C; V147 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; P148 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, N, Q,F, W, Y, or C; W149 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T,M, V, P, or C; L150 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;L151 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S152 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; F153 replaced with D, E, H,K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; K154 replaced with D, E, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; R155 replaced with D, E, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; G156 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; S157 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; A158 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;L159 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; E160 replacedwith H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; E161replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;K162 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;E163 replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, orC; N164 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P,or C; K165 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P,or C; I166 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L167replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; V168 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; K169 replaced with D, E, A, G, I,L, S, T, M, V, N, Q, F, W, Y, P, or C; E170 replaced with H, K, R, A, G,I, L, S, T, M, V, N, Q, F, W, Y, P, or C; T171 replaced with D, E, H, K,R, N, Q, F, W, Y, P, or C; G172 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; Y173 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M,V, P, or C; F174 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M,V, P, or C; F175 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M,V, P, or C; I176 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;Y177 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C;G178 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; Q179 replacedwith D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; V180replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L181 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; Y182 replaced with D, E, H, K, R,N, Q, A, G, I, L, S, T, M, V, P, or C; T183 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; D184 replaced with H, K, R, A, G, I, L, S, T, M,V, N, Q, F, W, Y, P, or C; K185 replaced with D, E, A, G, I, L, S, T, M,V, N, Q, F, W, Y, P, or C; T186 replaced with D, E, H, K, R, N, Q, F, W,Y, P, or C; Y187 replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M,V, P, or C; A188 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C;M189 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; G190 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; H191 replaced with D, E, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; L192 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; I193 replaced with D, E, H, K, R, N, Q, F,W, Y, P, or C; Q194 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V,F, W, Y, P, or C; R195 replaced with D, E, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; K196 replaced with D, E, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; K197 replaced with D, E, A, G, I, L, S, T, M, V, N, Q,F, W, Y, P, or C; V198 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC; H199 replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, orC; V200 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; F201replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; G202replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; D203 replaced withH, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; E204 replacedwith H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; L205replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S206 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; L207 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; V208 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; T209 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L210replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; F211 replaced withD, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; R212 replaced withD, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; C213 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or P; I214replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; Q215 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; N216 replacedwith D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; M217replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P218 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; E219replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;T220 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; L221 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; P222 replaced with D, E, H,K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; N223 replaced with D,E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; N224 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C; S225 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; C226 replaced with D, E, H,K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or P; Y227 replaced with D,E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; S228 replaced with D,E, H, K, R, N, Q, F, W, Y, P, or C; A229 replaced with D, E, H, K, R, N,Q, F, W, Y, P, or C; G230 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; I231 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A232replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; K233 replaced withD, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; L234 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; E235 replaced with H, K, R, A, G,I, L, S, T, M, V, N, Q, F, W, Y, P, or C; E236 replaced with H, K, R, A,G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; G237 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; D238 replaced with H, K, R, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; E239 replaced with H, K, R, A, G, I, L,S, T, M, V, N, Q, F, W, Y, P, or C; L240 replaced with D, E, H, K, R, N,Q, F, W, Y, P, or C; Q241 replaced with D, E, H, K, R, A, G, I, L, S, T,M, V, F, W, Y, P, or C; L242 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; A243 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; I244replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; P245 replaced withD, E, H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, or C; R246replaced with D, E, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C; E247replaced with H, K, R, A, G, I, L, S, T, M, V, N, Q, F, W, Y, P, or C;N248 replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, orC; A249 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; Q250replaced with D, E, H, K, R, A, G, I, L, S, T, M, V, F, W, Y, P, or C;I251 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; S252 replacedwith D, E, H, K, R, N, Q, F, W, Y, P, or C; L253 replaced with D, E, H,K, R, N, Q, F, W, Y, P, or C; D254 replaced with H, K, R, A, G, I, L, S,T, M, V, N, Q, F, W, Y, P, or C; G255 replaced with D, E, H, K, R, N, Q,F, W, Y, P, or C; D256 replaced with H, K, R, A, G, I, L, S, T, M, V, N,Q, F, W, Y, P, or C; V257 replaced with D, E, H, K, R, N, Q, F, W, Y, P,or C; T258 replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; F259replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; F260replaced with D, E, H, K, R, N, Q, A, G, I, L, S, T, M, V, P, or C; G261replaced with D, E, H, K, R, N, Q, F, W, Y, P, or C; A262 replaced withD, E, H, K, R, N, Q, F, W, Y, P, or C; L263 replaced with D, E, H, K, R,N, Q, F, W, Y, P, or C; K264 replaced with D, E, A, G, I, L, S, T, M, V,N, Q, F, W, Y, P, or C; L265 replaced with D, E, H, K, R, N, Q, F, W, Y,P, or C; and/or L266 replaced with D, E, H, K, R, N, Q, F, W, Y, P, orC.

[0163] In another embodiment, site directed changes at the amino acidlevel of BLyS can be made by replacing a particular amino acid with anon-conservative substitution. Antibodies of the present invention maybind BLyS amino acid sequences containing non-conservative substitutionmutations of the polypeptide of any one of SEQ ID NOS:3230-3237.

[0164] In an additional embodiment, antibodies of the present inventionbind BLyS polypeptides comprising, or alternatively consisting of, aBLyS amino acid sequence in which more than one amino acid (e.g., 2, 3,4, 5, 6, 7, 8, 9, 10, 15, 20, 30 and 50) is replaced with thesubstituted amino acids as described above (either conservative ornonconservative).

[0165] Replacement of amino acids can also change the selectivity of thebinding of a ligand to cell surface receptors. For example, Ostade etal., Nature 361:266-268 (1993) describes certain mutations resulting inselective binding of TNF-alpha to only one of the two known types of TNFreceptors. Since BLyS is a member of the TNF polypeptide family,mutations similar to those in TNF-alpha are likely to have similareffects in BLyS polypeptides.

[0166] Sites that are critical for ligand-receptor binding can also bedetermined by structural analysis such as crystallization, nuclearmagnetic resonance or photoaffinity labeling (Smith et al., J. Mol.Biol. 224:899-904 (1992) and de Vos et al. Science 255:306-312 (1992)).

[0167] Since BLyS is a member of the TNF-related protein family,mutations may be made in sequences encoding amino acids in the TNFconserved domain, e.g., in positions Gly-191 through Leu-284 of SEQ IDNO:3228 or in positions Gly-172 through Leu-265 of SEQ ID NO:3229, maymodulate rather than completely eliminate functional activities (e.g.,biological activities) of BLyS polypeptides or fragments or variantsthereof. Accordingly, antibodies of the present invention may bind BLySpolypeptides that have mutations in the TNF conserved domain. Inpreferred embodiments, antibodies of the present invention may bind BLySpolypeptides that have mutations in the TNF conserved domain and act asantagonists of BLyS. In other preferred embodiments, antibodies of thepresent invention may bind BLyS polypeptides that have mutations in theTNF conserved domain and act as agonists of BLyS.

[0168] Recombinant DNA technology known to those skilled in the art(see, for instance, DNA shuffling supra) can be used to create novelmutant proteins or muteins including single or multiple amino acidsubstitutions, deletions, additions or fusion proteins. Such modifiedpolypeptides can show, e.g., enhanced activity or increased stability.In addition, they may be purified in higher yields and show bettersolubility than the corresponding natural polypeptide, at least undercertain purification and storage conditions.

[0169] Thus, the invention also encompasses antibodies that bind BLySderivatives and analogs that have one or more amino acid residuesdeleted, added, or substituted to generate BLyS polypeptides, e.g., thatare better suited for expression, scale up, etc., in the host cells. Forexample, cysteine residues can be deleted or substituted with anotheramino acid residue in order to eliminate disulfide bridges; N-linkedglycosylation sites can be altered or eliminated to achieve, forexample, expression of a homogeneous product that is more easilyrecovered and purified from yeast hosts which are known tohyperglycosylate N-linked sites. To this end, a variety of amino acidsubstitutions at one or both of the first or third amino acid positionson any one or more of the glycosylation recognition sequences in theBLyS polypeptides of the invention, and/or an amino acid deletion at thesecond position of any one or more such recognition sequences willprevent glycosylation of the BLyS at the modified tripeptide sequence(see, e.g., Miyajimo et al., EMBO J 5(6):1193-1197). By way ofnon-limiting example, mutation of the serine at position 244 to alanineeither singly or in combination with mutation of the asparagine atposition 242 to glutamine abolishes glycosylation of the mature solubleform of BLyS (e.g., amino acids 134-285 of SEQ ID NO:3228) whenexpressed in the yeast Pichea pastoris. A mutant BLyS polypeptide inwhich only the asparagine at position 242 is mutated to glutamine, isstill gycosylated when expressed in Pichea pastoris. In this mutant, theglycosylation event may be due to the activation or unmasking of anO-linked glyscosylation site at serine 244. Similar mutations affectingglycosylation could also be made in the BLyS polypeptide of SEQ IDNO:3229, i.e., aspargine-223 to glutamine and/or serine-224 to alanineof SEQ ID NO:3229. Additionally, one or more of the amino acid residuesof the polypeptides of the invention (e.g., arginine and lysineresidues) may be deleted or substituted with another residue toeliminate undesired processing by proteases such as, for example, furinsor kexins. One possible result of such a mutation is that BLySpolypeptide of the invention is not cleaved and released from the cellsurface. Accordingly, antibodies of the invention may bind BLySderivatives and analogs that have one or more amino acid residuesdeleted, added, or substituted. In other embodiments, antibodies of theinvention may bind BLyS derivatives, variants or analogs that are unableto be cleaved from the cell surface.

[0170] In a specific embodiment, antibodies of the invention bind BLySpolypeptides in which Lys-132 and/or Arg-133 of the BLyS sequence shownin SEQ ID NO:3228 is mutated to another amino acid residue, or deletedaltogether, to prevent or diminish release of the soluble form of BLySfrom cells expressing BLyS. In a more specific embodiment, antibodies ofthe invention bind BLyS polypeptides in which Lys-132 of the BLySsequence shown in SEQ ID NO:3228 is mutated to Ala-132. In another,nonexclusive specific embodiment, antibodies of the invention bind BLySpolypeptides in which Arg-133 of the BLyS sequence shown in SEQ IDNO:3228 is mutated to Ala-133. These mutated proteins, and/or have usessuch as, for example, in ex vivo therapy or gene therapy, to engineercells expressing a BLyS polypeptide that is retained on the surface ofthe engineered cells.

[0171] In a specific embodiment, antibodies of the invention bind BLySpolypeptides in which Cys-146 of the BLyS sequence shown in SEQ IDNO:3228 is mutated to another amino acid residue, or deleted altogether,for example, to aid preventing or diminishing oligomerization of themutant BLyS polypeptide when expressed in an expression system. In aspecific embodiment, antibodies of the invention bind BLyS polypeptidesin which Cys-146 is replaced with a serine amino acid residue.

[0172] In another specific embodiment, antibodies of the invention bindBLyS polypeptides in which Cys-232 of the BLyS sequence shown in SEQ IDNO:3228 is mutated to another amino acid residue, or deleted altogether,for example, to aid preventing or diminishing oligomerization of themutant BLyS polypeptide when expressed in an expression system. In aspecific embodiment, antibodies of the invention bind BLyS polypeptidesin which Cys-232 is replaced with a serine amino acid residue.Polypeptides encoding these polypeptides are also encompassed by theinvention.

[0173] In yet another specific embodiment, antibodies of the inventionbind BLyS polypeptides in which Cys-245 of the BLyS sequence shown inSEQ ID NO:3228 is mutated to another amino acid residue, or deletedaltogether, for example, to aid preventing or diminishingoligomerization of the mutant BLyS polypeptide when expressed in anexpression system. In a specific embodiment, antibodies of the inventionbind BLyS polypeptides in which Cys-245 is replaced with a serine aminoacid residue. Polypeptides encoding these polypeptides are alsoencompassed by the invention.

[0174] The polypeptides of the present invention are preferably providedin an isolated form, and preferably are substantially purified. Arecombinantly produced version of the BLyS polypeptides can besubstantially purified by the one-step method described in Smith andJohnson, Gene 67:31-40 (1988).

[0175] The antibodies of the present invention bind BLyS polypeptidesincluding the complete polypeptide encoded by the deposited cDNA (ATCCDeposit No. 97768) including the intracellular, transmembrane andextracellular domains of the polypeptide encoded by the deposited cDNA,the mature soluble polypeptide encoded by the deposited cDNA, theextracellular domain minus the intracellular and transmembrane domainsof the protein, the complete polypeptide of SEQ ID NO:3228, the maturesoluble polypeptide of SEQ ID NO:3228, e.g., amino acids 134-285 of SEQID NO:3228, the extracellular domain of SEQ ID NO:3228, amino acidresidues 73-285 of SEQ ID NO:3228 minus the intracellular andtransmembrane domains, as well as polypeptides which have at least 80%,85%, 90% similarity, more preferably at least 95% similarity, and stillmore preferably at least 96%, 97%, 98% or 99% similarity to thosedescribed above. Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

[0176] The antibodies of the present invention bind BLyS polypeptidesincluding the complete polypeptide encoded by the deposited cDNAincluding the intracellular, transmembrane and extracellular domains ofthe polypeptide encoded by the deposited cDNA (ATCC Deposit No. 203518),the mature soluble polypeptide encoded by the deposited cDNA, theextracellular domain minus the intracellular and transmembrane domainsof the protein, the complete polypeptide of SEQ ID NO:3229, the maturesoluble of SEQ ID NO:3229, e.g., amino acid residues 134-266 of SEQ IDNO:3229, the extracellular domain of SEQ ID NO:3229, e.g., amino acidresidues 73-266 of SEQ ID NO:3229 minus the intracellular andtransmembrane domains, as well as polypeptides which have at least 80%,85%, 90% similarity, more preferably at least 95% similarity, and stillmore preferably at least 96%, 97%, 98% or 99% similarity to thosedescribed above. Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

[0177] Further antibodies of the present invention bind polypeptidesincluding polypeptides at least 80%, or at least 85% identical, morepreferably at least 90% or 95% identical, still more preferably at least96%, 97%, 98% or 99% identical to the polypeptide encoded by thedeposited cDNA (ATCC Deposit No. 97768) or to the polypeptide of SEQ IDNO:3228, and also include antibodies that bind portions of suchpolypeptides with at least 30 amino acids and more preferably at least50 amino acids.

[0178] Further antibodies of the present invention bind polypeptidesincluding polypeptides at least 80%, or at least 85% identical, morepreferably at least 90% or 95% identical, still more preferably at least96%, 97%, 98% or 99% identical to the polypeptide encoded by thedeposited cDNA (ATCC Deposit No. 203518) or to the polypeptide of SEQ IDNO:3229, and also include antibodies that bind portions of suchpolypeptides with at least 30 amino acids and more preferably at least50 amino acids. Polynucleotides encoding these polypeptides are alsoencompassed by the invention.

[0179] By “% similarity” for two polypeptides is intended a similarityscore produced by comparing the amino acid sequences of the twopolypeptides using the Bestfit program (Wisconsin Sequence AnalysisPackage, Version 8 for Unix, Genetics Computer Group, UniversityResearch Park, 575 Science Drive, Madison, Wis. 53711) and the defaultsettings for determining similarity. Bestfit uses the local homologyalgorithm of Smith and Waterman (Advances in Applied Mathematics2:482-489, 1981) to find the best segment of similarity between twosequences.

[0180] By a polypeptide having an amino acid sequence at least, forexample, 95% “identical” to a reference amino acid sequence of a BLySpolypeptide is intended that the amino acid sequence of the polypeptideis identical to the reference sequence except that the polypeptidesequence may include up to five amino acid alterations per each 100amino acids of the reference amino acid of the BLyS polypeptide. Inother words, to obtain a polypeptide having an amino acid sequence atleast 95% identical to a reference amino acid sequence, up to 5% of theamino acid residues in the reference sequence may be deleted orsubstituted with another amino acid, or a number of amino acids up to 5%of the total amino acid residues in the reference sequence may beinserted into the reference sequence. These alterations of the referencesequence may occur at the amino or carboxy terminal positions of thereference amino acid sequence or anywhere between those terminalpositions, interspersed either individually among residues in thereference sequence or in one or more contiguous groups within thereference sequence.

[0181] As a practical matter, whether any particular polypeptide is atleast 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, forinstance, the amino acid sequence of SEQ ID NO:3228, the amino acidsequence encoded by the deposited cDNA clone HNEDU15 (ATCC Accession No.97768), or fragments thereof, or, for instance, to the amino acidsequence of SEQ ID NO:3229, the amino acid sequence encoded by thedeposited cDNA clone HDPMC52 (ATCC Accession No. 203518), or fragmentsthereof, can be determined conventionally using known computer programssuch the Bestfit program (Wisconsin Sequence Analysis Package, Version 8for Unix, Genetics Computer Group, University Research Park, 575 ScienceDrive, Madison, Wis. 53711). When using Bestfit or any other sequencealignment program to determine whether a particular sequence is, forinstance, 95% identical to a reference sequence according to the presentinvention, the parameters are set, of course, such that the percentageof identity is calculated over the full length of the reference aminoacid sequence and that gaps in homology of up to 5% of the total numberof amino acid residues in the reference sequence are allowed.

[0182] In a specific embodiment, the identity between a reference(query) sequence (a sequence of the present invention) and a subjectsequence, also referred to as a global sequence alignment, is determinedusing the FASTDB computer program based on the algorithm of Brutlag etal. (Comp. App. Biosci. 6:237-245 (1990)). Preferred parameters used ina FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, MismatchPenalty=1, Joining Penalty=20, Randomization Group Length=0, CutoffScore=1, Window Size=sequence length, Gap Penalty=5, Gap SizePenalty=0.05, Window Size=500 or the length of the subject amino acidsequence, whichever is shorter. According to this embodiment, if thesubject sequence is shorter than the query sequence due to N- orC-terminal deletions, not because of internal deletions, a manualcorrection is made to the results to take into consideration the factthat the FASTDB program does not account for N- and C-terminaltruncations of the subject sequence when calculating global percentidentity. For subject sequences truncated at the N- and C-termini,relative to the query sequence, the percent identity is corrected bycalculating the number of residues of the query sequence that are N- andC-terminal of the subject sequence, which are not matched/aligned with acorresponding subject residue, as a percent of the total bases of thequery sequence. A determination of whether a residue is matched/alignedis determined by results of the FASTDB sequence alignment. Thispercentage is then subtracted from the percent identity, calculated bythe above FASTDB program using the specified parameters, to arrive at afinal percent identity score. This final percent identity score is whatis used for the purposes of this embodiment. Only residues to the N- andC-termini of the subject sequence, which are not matched/aligned withthe query sequence, are considered for the purposes of manuallyadjusting the percent identity score. That is, only query residuepositions outside the farthest N- and C-terminal residues of the subjectsequence. For example, a 90 amino acid residue subject sequence isaligned with a 100 residue query sequence to determine percent identity.The deletion occurs at the N-terminus of the subject sequence andtherefore, the FASTDB alignment does not show a matching/alignment ofthe first 10 residues at the N-terminus. The 10 unpaired residuesrepresent 10% of the sequence (number of residues at the N- andC-termini not matched/total number of residues in the query sequence) so10% is subtracted from the percent identity score calculated by theFASTDB program. If the remaining 90 residues were perfectly matched thefinal percent identity would be 90%. In another example, a 90 residuesubject sequence is compared with a 100 residue query sequence. Thistime the deletions are internal deletions so there are no residues atthe N- or C-termini of the subject sequence which are notmatched/aligned with the query. In this case the percent identitycalculated by FASTDB is not manually corrected. Once again, only residuepositions outside the N- and C-terminal ends of the subject sequence, asdisplayed in the FASTDB alignment, which are not matched/aligned withthe query sequence are manually corrected for. No other manualcorrections are made for the purposes of this embodiment.

[0183] Antibodies that Immunospecifically bind BLyS Polypeptides

[0184] The present invention also encompasses antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to BLyS polypeptides,which antibodies comprise, or alternatively consist of, all or a portionof a heavy and/or light chain variable domain of the scFvs referred toin Table 1.

[0185] The present invention also encompasses methods and compositionsfor detecting, diagnosing and/or prognosing diseases or disordersassociated with aberrant BLyS or BLyS receptor expression orinappropriate BLyS or BLyS receptor function in an animal, preferably amammal, and most preferably a human, comprising using antibodies(including molecules which comprise, or alternatively consist of,antibody fragments or variants thereof) that immunospecifically bind toBLyS. Diseases and disorders which can be detected, diagnosed orprognosed with the antibodies of the invention include, but are notlimited to, immune disorders (e.g., lupus, rheumatoid arthritis,multiple sclerosis, myasthenia gravis, Hashimoto's disease, andimmunodeficiency syndrome), inflammatory disorders (e.g., asthma,allergic disorders, and rheumatoid arthritis), infectious diseases(e.g., AIDS), and proliferative disorders (e.g., leukemia, carcinoma,and lymphoma).

[0186] The present invention further encompasses methods andcompositions for preventing, treating or ameliorating diseases ordisorders associated with aberrant BLyS or BLyS receptor expression orinappropriate BLyS or BLyS receptor function in an animal, preferably amammal, and most preferably a human, comprising administering to saidanimal an effective amount of one or more antibodies (includingmolecules which comprise, or alternatively consist of, antibodyfragments or variants thereof) that immunospecifically bind to BLyS.Diseases and disorders which can be prevented, treated or inhibited byadministering an effective amount of one or more antibodies or moleculesof the invention include, but are not limited to, immune disorders(e.g., lupus, rheumatoid arthritis, multiple sclerosis, myastheniagravis, Hashimoto's disease, and immunodeficiency syndrome),inflammatory disorders (e.g., asthma, allergic disorders, and rheumatoidarthritis), infectious diseases (e.g., AIDS), and proliferativedisorders (e.g., leukemia, carcinoma, and lymphoma).

[0187] Anti-BLyS Antibodies

[0188] The antibodies of the present invention were discovered, in part,using phage display technology. Single chain antibody molecules(“scFvs”) displayed on the surface of phage particles were screened toidentify those scFvs that immunospecifically bind to BLyS, including themembrane-bound form and soluble form of BLyS. The present inventionencompasses the scFvs and portions thereof that were identified toimmunospecifically bind to BLyS, including scFvs that immunospecificallybind to the soluble form of BLyS, scFvs that immunospecifically bind tothe membrane-bound form of BLyS, and scFvs that immunospecifically bindto both the soluble form and membrane-bound form of BLyS. In particular,the present invention encompasses scFvs comprising, or alternativelyconsisting of, the amino acid sequence of SEQ ID NOS: 1-2128, asreferred to in Table 1. Preferably, the scFvs of the present inventioncomprise, or alternatively consist of, the amino acid sequence of SEQ IDNOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908. The scFvs includescFvs that bind to soluble BLyS (e.g., scFvs comprising, oralternatively consisting of, an amino acid sequence of SEQ ID NOS:1563-1880), scFvs that bind to the membrane-bound form of BLyS (e.g.,scFvs comprising, or alternatively consisting of, an amino acid sequenceof SEQ ID NOS: 1881-2128), and scFvs that bind to both the soluble formand the membrane-bound form of BLyS (e.g., scFvs comprising, oralternatively consisting of, an amino acid sequence of SEQ ID NOS:1-1562). Molecules comprising, or alternatively consisting of, fragmentsor variants of these scFvs, that immunospecifically bind to BLyS arealso encompassed by the invention, as are nucleic acid moleculesencoding these scFvs, molecules, fragments and/or variants.

[0189] In one embodiment of the present invention, scFvs thatimmunospecifically bind to BLyS comprise a polypeptide having the aminoacid sequence of any one of the VH domains referred to in Table 1 and/orany one of the VL domains referred to in Table 1. In preferredembodiments, scFvs of the present invention comprise the amino acidsequence of a VH domain and VL domain from the same scFv referred to inTable 1. In alternative embodiments, scFvs of the present inventioncomprise the amino acid sequence of a VH domain and VL domain fromdifferent scFvs referred to in Table 1. In another embodiment, scFvsthat immunospecifically bind to BLyS, comprise a polypeptide having theamino acid sequence of any one, two, three, or more of the VH CDRsreferred to in Table 1 and/or any one, two, three, or more of the VLCDRs referred to in Table 1. In preferred embodiments, scFvs of thepresent invention comprise the amino acid sequence of a VH CDR and VLCDR from the same scFv referred to in Table 1. In alternativeembodiments, scFvs of the present invention comprise the amino acidsequence of a VH CDR and VL CDR from different scFvs referred to inTable 1. Molecules comprising, or alternatively consisting of, antibodyfragments or variants of the scFvs referred to in Table 1 thatimmunospecifically bind to BLyS are also encompassed by the invention,as are nucleic acid molecules encoding these scFvs, molecules, fragmentsand/or variants.

[0190] (Table 1 can be found at the end of the specification just priorto the claims.)

[0191] In another embodiment of the present invention, an scFv thatimmunospecifically binds to a soluble form of BLyS, comprises, oralternatively consists of, the amino acid sequence of SEQ IDNOS:1563-1880 as referred to in Table 1. In a preferred embodiment, anscFv that immunospecifically binds to a soluble form of BLyS comprises,or alternatively consists of, the amino acid sequence of SEQ ID NOS:1570-1595. In an even more preferred embodiment, an scFv thatimmunospecifically binds to a soluble form of BLyS comprises, oralternatively consists of, the amino acid sequence of SEQ IDNOS:1563-1569.

[0192] In another embodiment of the present invention, an scFv thatimmunospecifically binds to a membrane-bound form of BLyS comprises, oralternatively consists of, the amino acid sequence of SEQ IDNOS:1881-2128 as referred to in Table 1. In a preferred embodiment, anscFv that immunospecifically binds to a membrane-bound form of BLyScomprises, or alternatively consists of, the amino acid sequence of SEQID NOS:1886-1908. In an even more preferred embodiment, an scFv thatimmunospecifically binds to a membrane-bound form of BLyS comprises, oralternatively consists of, the amino acid sequence of SEQ IDNOS:1881-1885.

[0193] In another embodiment of the present invention, an scFv thatimmunospecifically binds to both the soluble form and membrane-boundform of BLyS comprises, or alternatively consists of, the amino acidsequence of SEQ ID NOS:1-1562 as referred to in Table 1. In a preferredembodiment, an scFv that immunospecifically binds to both the solubleform and membrane-bound form of BLyS comprises, or alternativelyconsists of, the amino acid sequence of SEQ ID NOS:834-872. In anotherpreferred embodiment, an scFv that immunospecifically binds to both thesoluble form and membrane-bound form of BLyS comprises, or alternativelyconsists of, any one of the amino acids sequences of SEQ ID NOS:1-46 or321-329. Molecules comprising, or alternatively consisting of, fragmentsor variants of these scFvs, that immunospecifically bind to the solubleform of BLyS and/or the membrane-bound form of BLyS are also encompassedby the invention, as are nucleic acid molecules encoding these scFvs,molecules, fragments and/or variants.

[0194] In another embodiment of the present invention, scFvs thatimmunospecifically bind to the soluble form of BLyS, comprise apolypeptide having the amino acid sequence of any one of the VH domainscontained in SEQ ID NOS:1563-1880 as disclosed in Table 1 and/or any oneof the VL domains contained in SEQ ID NOS:1563-1880 as disclosed inTable 1. In preferred embodiments, scFvs of the present invention thatimmunospecifically bind to the soluble form of BLyS, comprise apolypeptide having the amino acid sequence of a VH CDR and VL CDR fromthe same scFv referred to in Table 1. In alternative embodiments, scFvsof the present invention that immunospecifically bind to the solubleform of BLyS, comprise a polypeptide having amino acid sequence of a VHCDR and VL CDR from different scFvs referred to in Table 1. In anotherembodiment, scFvs that immunospecifically bind to the soluble form ofBLyS, comprise a polypeptide having the amino acid sequence of any one,two, three, or more of the VH CDRs SEQ ID NOS:1563-1880 as disclosed inTable 1 and/or any one, two, three, or more of the VL CDRs contained incontained SEQ ID NOS:1563-1880, as disclosed in Table 1. In preferredembodiments, scFvs of the present invention that immunospecifically bindto the soluble form of BLyS, comprise a polypeptide having the aminoacid sequence of a VH domain and VL domain from the same scFv referredto in Table 1. In alternative embodiments, scFvs of the presentinvention that immunospecifically bind to the soluble form of BLyS,comprise a polypeptide having the of the amino acid sequence of a VHdomain and VL domain from different scFvs referred to in Table 1. In apreferred embodiment, scFvs that immunospecifically bind to the solubleform of BLyS, comprise a polypeptide having the amino acid sequence ofany one of the VH CDR3s contained in SEQ ID NOS:1563-1880 as disclosedin Table 1 and/or any one of the VL CDR3s contained in SEQ ID NOS:1563-1880 as disclosed in Table 1. In preferred embodiments, scFvs ofthe present invention that immunospecifically bind to the soluble formof BLyS, comprise a polypeptide having the amino acid sequence of a VHCDR and VL CDR from the same scFv referred to in Table 1. In alternativeembodiments, scFvs of the present invention that immunospecifically bindto the soluble form of BLyS, comprise a polypeptide having the aminoacid sequence of a VH CDR and VL CDR from different scFvs referred to inTable 1. Molecules comprising, or alternatively consisting of, fragmentsor variants of these scFvs, that immunospecifically bind to BLyS,preferably the soluble form of BLyS, are also encompassed by theinvention, as are nucleic acid molecules encoding these scFvs,molecules, fragments and/or variants.

[0195] In another embodiment of the present invention, scFvs thatimmunospecifically bind to the membrane-bound form of BLyS comprise apolypeptide having the amino acid sequence of any one of the VH domainscontained in SEQ ID NOS:1881-2128 as disclosed in Table 1 and/or any oneof the VL domains contained in SEQ ID NOS: 1881-2128 as disclosed inTable 1. In preferred embodiments, scFvs of the present invention thatimmunospecifically bind to the soluble form of BLyS, comprise apolypeptide having the amino acid sequence of a VH CDR and VL CDR fromthe same scFv referred to in Table 1. In alternative embodiments, scFvsof the present invention that immunospecifically bind to themembrane-bound form of BLyS, comprise a polypeptide having the aminoacid sequence of a VH domain and VL domain from different scFvs referredto in Table 1. In another embodiment, scFvs that immunospecifically bindto the membrane-bound form of BLyS, comprise a polypeptide having theamino acid sequence of any one, two, three, or more of the VH CDRscontained in SEQ ID NOS: 1881-2128 as disclosed in Table 1 and/or anyone, two, three, or more of the VL CDRs contained in SEQ ID NOS:1881-2128 as disclosed in Table 1. In preferred embodiments, scFvs ofthe present invention that immunospecifically bind to the membrane-boundform of BLyS, comprise a polypeptide having the amino acid sequence of aVH domain and VL domain from the same scFv referred to in Table 1. Inalternative embodiments, scFvs of the present invention thatimmunospecifically bind to the membrane-bound form of BLyS, comprise apolypeptide having the amino acid sequence of a VH domain and VL domainfrom different scFvs referred to in Table 1. In a preferred embodiment,scFvs that immunospecifically bind to the membrane-bound form of BLyS,comprise a polypeptide having the amino acid sequence of any one of theVH CDR3s contained in SEQ ID NOS: 1881-2128 as disclosed in Table 1and/or any one of the VL CDR3s contained in SEQ ID NOS: 1881-2128 asdisclosed in Table 1. In preferred embodiments, scFvs of the presentinvention that immunospecifically bind to the membrane-bound form ofBLyS, comprise a polypeptide having the amino acid sequence of a VHdomain and VL domain from the same scFv referred to in Table 1. Inalternative embodiments, scFvs of the present invention thatimmunospecifically bind to the membrane-bound form of BLyS, comprise apolypeptide having the amino acid sequence of a VH CDR and VL CDR fromdifferent scFvs referred to in Table 1. Molecules comprising, oralternatively consisting of, fragments or variants of these scFvs, thatimmunospecifically bind to BLyS, preferably the membrane-bound form ofBLyS, are also encompassed by the invention, as are nucleic acidmolecules encoding these scFvs, molecules, fragments and/or variants.

[0196] In another embodiment of the present invention, scFvs thatimmunospecifically bind to the soluble form and membrane-bound form ofBLyS, comprise a polypeptide having the amino acid sequence of any oneof the VH domains contained in SEQ ID NOS:1-1562 as disclosed in Table 1and/or any one of the VL domains contained in SEQ ID NOS:1-1562 asdisclosed in Table 1. In preferred embodiments, scFvs of the presentinvention that immunospecifically bind to the soluble and membrane-boundforms of BLyS, comprise a polypeptide having the amino acid sequence ofa VH domain and VL domain from the same scFv referred to in Table 1. Inalternative embodiments, scFvs of the present invention thatimmunospecifically bind to the soluble form and membrane-bound form ofBLyS, comprise a polypeptide having the amino acid sequence of a VHdomain and VL domain from different scFvs referred to in Table 1. Inanother embodiment, scFvs that immunospecifically bind to the solubleform and membrane-bound form of BLyS comprise a polypeptide having theamino acid sequence of any one, two, three, or more of the VH CDRscontained in SEQ ID NOS:1-1562 as disclosed in Table 1 and/or any one,two, three, or more of the VL CDRs contained in SEQ ID NOS:1-1562 asdisclosed in Table 1. In preferred embodiments, scFvs of the presentinvention that immunospecifically bind to the soluble form andmembrane-bound form of BLyS, comprise a polypeptide having the aminoacid sequence of a VH domain and VL domain from the same scFv referredto in Table 1. In alternative embodiments, scFvs of the presentinvention that immunospecifically bind to the soluble and membrane-boundforms of BLyS, comprise a polypeptide having the amino acid sequence ofa VH domain and VL domain from different scFvs referred to in Table 1.In a preferred embodiment, scFvs that immunospecifically bind to thesoluble and membrane-bound forms of BLyS, comprise a polypeptide havingthe amino acid sequence of any one of the VH CDR3s contained in SEQ IDNOS:1-1562 as disclosed in Table 1 and/or any one of the VL CDR3scontained in SEQ ID NOS:1-1562, as disclosed in Table 1. In preferredembodiments, scFvs of the present invention that immunospecifically bindto the soluble and membrane-bound forms of BLyS, comprise a polypeptidehaving the amino acid sequence of a VH CDR and VL CDR from the same scFvreferred to in Table 1. In alternative embodiments, scFvs of the presentinvention that immunospecifically bind to the soluble and membrane-boundforms of BLyS, comprise a polypeptide having the amino acid sequence ofa VH CDR and VL CDR from different scFvs referred to in Table 1.Molecules comprising, or alternatively consisting of, fragments orvariants of these scFvs or molecules, that immunospecifically bind toBLyS, preferably the soluble and membrane-bound forms of BLyS, are alsoencompassed by the invention, as are nucleic acid molecules encodingthese scFvs, molecules, fragments and/or variants.

[0197] The present invention provides antibodies (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) that immunospecifically bind to a polypeptide or apolypeptide fragment of BLyS. In particular, the invention providesantibodies corresponding to the scFvs referred to in Table 1, such scFvsmay routinely be “converted” to immunoglobulin molecules by inserting,for example, the nucleotide sequences encoding the VH and/or VL domainsof the scFv into an expression vector containing the constant domainsequences and engineered to direct the expression of the immunoglobulinmolecule, as described in more detail in Example 20, infra.

[0198] In one embodiment, the invention provides antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) wherein said antibodies comprise, or alternativelyconsist of, a polypeptide having an amino acid sequence of any one ofthe VH domains contained in the sequences referred to in Table 1. Thepresent invention also provides antibodies that immunospecifically bindto a polypeptide, or polypeptide fragment of BLyS, wherein saidantibodies comprise, or alternatively consist of, a polypeptide havingan amino acid sequence of any one, two, three, or more of the VH CDRscontained in the sequences referred to in Table 1. Molecules comprising,or alternatively consisting of, these antibodies, or antibody fragmentsor variants thereof, that immunospecifically bind to BLyS or a BLySfragment are also encompassed by the invention, as are nucleic acidmolecules encoding these antibodies, molecules, fragments and/orvariants.

[0199] In one embodiment of the present invention, antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind BLyS, comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof a VH CDR referred to in Table 1. In particular, the inventionprovides antibodies that immunospecifically bind BLyS, comprising, oralternatively consisting of, a polypeptide having the amino acidsequence of a VH CDR1 contained in SEQ ID NOS:1-46, 321-329, 1563-1569,or 1881-1885 as disclosed in Table 1. In another embodiment, antibodiesthat immunospecifically bind BLyS, comprise, or alternatively consistof, a polypeptide having the amino acid sequence of a VH CDR2 containedin SEQ ID NOS:1-46, 321-329, 1563-1569, or 1881-1885 as disclosed inTable 1. In a preferred embodiment, antibodies that immunospecificallybind BLyS, comprise, or alternatively consist of a polypeptide havingthe amino acid sequence of a VH CDR3 contained in SEQ ID NOS:1-46,321-329, 1563-1569, or 1881-1885 as disclosed in Table 1. In yet anotherembodiment, antibodies that immunospecifically bind BLyS, comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof a VH CDR1 contained in SEQ ID NOS:834-872, 1570-1595, or 1886-1908 asdisclosed in Table 1; a VH CDR2 contained in SEQ ID NOS: SEQ ID NOS: SEQID NOS:834-872, 1570-1595, or 1886-1908; and/or a VH CDR3 contained inSEQ ID NOS: SEQ ID NOS:834-872, 1570-1595, or 1886-1908 as disclosed inTable 1. Preferably, antibodies of the invention comprise, oralternatively consist of, VH CDRs that are derived from the same scFv asdisclosed in Table 1. Molecules comprising, or alternatively consistingof, fragments or variants of these antibodies that immunospecificallybind to BLyS are also encompassed by the invention, as are nucleic acidmolecules encoding these antibodies, molecules, fragments or variants.

[0200] The present invention provides antibodies (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants) that immunospecifically bind to a polypeptide, or polypeptidefragment of BLyS. In particular, the invention provides antibodieswherein said antibodies comprise, or alternatively consist of, a VLdomain having an amino acid sequence of any one of the VL domainsreferred to in Table 1. The present invention also provides antibodiesthat immunospecifically bind to a polypeptide or polypeptide fragment ofBLyS, wherein said antibodies comprise, or alternatively consist of, aVL CDR having an amino acid sequence of any one, two, three, or more ofthe VL CDRs contained in the sequences referred to in Table 1. Moleculescomprising, or alternatively consisting of, fragments or variants ofthese antibodies that immunospecifically bind to BLyS are alsoencompassed by the invention, as are nucleic acid molecules encodingthese antibodies, molecules, fragments or variants.

[0201] In one embodiment of the present invention, antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind BLyS, comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof a VL CDR referred to in Table 1. In particular, the inventionprovides antibodies that immunospecifically bind BLyS, comprising, oralternatively consisting of, a polypeptide having the amino acidsequence of a VL CDR1 contained in SEQ ID NOS:1-46, 321-329, 1563-1569,or 1881-1885 as disclosed in Table 1. In another embodiment, antibodiesthat immunospecifically bind BLyS comprise, or alternatively consist of,a polypeptide having the amino acid sequence of a VL CDR2 contained inSEQ ID NOS:1-46, 321-329, 1563-1569, or 1881-1885 as disclosed inTable 1. In a preferred embodiment, antibodies comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof a VL CDR3 contained in SEQ ID NOS: in SEQ ID NOS:1-46, 321-329,1563-1569, or 1881-1885 disclosed in Table 1. In yet another embodiment,antibodies that immnospecifically bind BLyS comprise, or alternativelyconsist of: a polypeptide having the amino acid sequence of a VL CDR1contained in SEQ ID NOS:834-872, 1570-1595, or 1886-1908 as disclosed inTable 1; a VL CDR2 SEQ ID NOS:834-872, 1570-1595, or 1886-1908 asdisclosed in Table 1; and a VL CDR3 contained SEQ ID NOS:834-872,1570-1595, or 1886-1908 as disclosed in Table 1. Preferably, antibodiesof the invention comprise, or alternatively consist of, VL CDRs that arederived from the same scFv as disclosed in Table 1. Moleculescomprising, or alternatively consisting of, fragments or variants ofthese antibodies, that immunospecifically bind to BLyS are alsoencompassed by the invention, as are nucleic acid molecules encodingthese antibodies, molecules, fragments or variants.

[0202] The present invention also provides antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to a polypeptide or apolypeptide fragment of BLyS, wherein said antibodies comprise, oralternatively consist of, a VH domain of one of the scFvs referred to inTable 1 combined with a VL domain of one of the scFvs referred to inTable 1, or other VL domain. The present invention further providesantibodies (including molecules comprise, or alternatively consist of,antibody fragments or variants thereof) that immunospecifically bind toa polypeptide or a polypeptide fragment of BLyS, wherein said antibodiescomprise, or alternatively consist of, a VL domain of one of the scFvsreferred to in Table 1 combined with a VH domain of one of the scFvsreferred to in Table 1, or other VH domain. In a preferred embodiment,antibodies that immunospecifically bind to a polypeptide or apolypeptide fragment of BLyS, comprise, or alternatively consist of, apolypeptide having the amino acid sequence of a VH domain contained SEQID NOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908 as disclosed inTable 1 and a VL domain contained in contained SEQ ID NOS:1-46, 321-329,834-872, 1563-1595, or 1881-1908 as disclosed in Table 1. In a furtherpreferred embodiment, the antibodies of the invention comprise, oralternatively consist of, a VH and a VL domain from the same scFv asdisclosed in Table 1. Molecules comprising, or alternatively consistingof, fragments or variants of these antibodies, that immunospecificallybind to BLyS are also encompassed by the invention, as are nucleic acidmolecules encoding these antibodies, molecules, fragments or variants.

[0203] The present invention also provides antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants) that immunospecifically bind to a polypeptide orpolypeptide fragment of BLyS, wherein said antibodies comprise, oralternatively consist of, one, two, three, or more VH CDRs and one, two,three or more VL CDRs, as referred to in Table 1. In particular, theinvention provides for antibodies that immunospecifically bind to apolypeptide or polypeptide fragment of BLyS, wherein said antibodiescomprise, or alternatively consist of, a VH CDR1 and a VL CDR1, a VHCDR1 and a VL CDR2, a VH CDR1 and a VL CDR3, a VH CDR2 and a VL CDR1, VHCDR2 and VL CDR2, a VH CDR2 and a VL CDR3, a VH CDR3 and a VH CDR1, a VHCDR3 and a VL CDR2, a VH CDR3 and a VL CDR3, or any combination thereof,of the VH CDRs and VL CDRs referred to in Table 1. In a preferredembodiment, one or more of these combinations are from the same scFv asdisclosed in Table 1. Molecules comprising, or alternatively consistingof, fragments or variants of these antibodies, that immunospecificallybind to BLyS are also encompassed by the invention, as are nucleic acidmolecules encoding these antibodies, molecules, fragments or variants.

[0204] In a preferred embodiment the invention provides antibodieswherein the VH CDRX (where X=1, 2, or 3) and VL CDRY (where Y=1, 2, or3) are from scFvs with the same specificity (i.e., from scFvs that bindsoluble BLyS, from scFvs that bind membrane-bound BLyS, or from scFvsthat bind both soluble and membrane-bound BLyS. Molecules comprising, oralternatively consisting of, fragments or variants of these antibodies,that immunospecifically bind to BLyS are also encompassed by theinvention, as are nucleic acid molecules encoding these antibodies,molecules, fragments or variants.

[0205] The term “antibody,” as used herein, refers to immunoglobulinmolecules and immunologically active portions of immunoglobulinmolecules, i.e., molecules that contain an antigen binding site thatimmunospecifically binds an antigen. As such, the term “antibody”encompasses not only whole antibody molecules, but also antibodyfragments, as well as variants (including derivatives) of antibodies andantibody fragments. Antibodies of the invention include, but are notlimited to, monoclonal, multispecific, human or chimeric antibodies,single chain antibodies, single chain Fvs (scFvs), Fab fragments,F(ab′)₂ fragments, Fd fragments, disulfide-linked Fvs (sdFvs),antiidiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodiesto antibodies of the invention), and epitope-binding fragments of any ofthe above. The immunoglobulin molecules of the invention can be of anytype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG₁, IgG₂,IgG₃, IgG₄, IgA₁ and IgA₂) or subclass of immunoglobulin molecule. Theantibodies of the present invention also include molecules comprising,or alternatively consisting of, a polypeptide having an amino acidsequence of a portion of an amino acid sequence contained SEQ IDNOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908. Preferably, anantibody of the invention comprises, or alternatively consists of, apolypeptide having an amino acid sequence of a VH domain, VH CDR, VLdomain, or VL CDR of any one those contained in the sequences referredto in Table 1. Antibodies of the invention also include moleculescomprising, or alternatively consisting of, fragments or variants of theabove antibodies that immunospecifically bind BLyS.

[0206] Most preferably the antibodies of the present invention are wholeantibodies or antibody fragments that immunospecifically bind humanBLyS. Antibody fragments of the invention that immunospecifically bindhuman BLyS include, but are not limited to, Fab, Fab′ and F(ab′)₂, Fdfragments, single-chain Fvs (scFv), single-chain antibodies,disulfide-linked Fvs (sdFvs), fragments comprising, or alternativelyconsisting of, either a VL or VH domain, and epitope binding fragmentsof any of the above.

[0207] BLyS-binding antibody fragments, including single-chainantibodies, may comprise, or alternatively consist of, the variableregion(s) alone or in combination with the entirety or a portion of thefollowing: hinge region, CH1, CH2, and CH3 domains. In a preferredembodiment, the antibodies of the invention comprise, or alternativelyconsist of, a polypeptide that immunospecifically binds to BLyS, saidpolypeptides comprise, or alternatively consist of, one, two, three,four, five, six or more CDRs referred to in Table 1, preferably apolypeptide having an amino acid sequence of a VH CDR3 and/or a VL CDR3of contained SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908as disclosed in Table 1. Most preferably, antibodies of the inventioncomprise, or alternatively consist of, one, two, three, four, five, sixor more CDRs from the same scFv, as referred to in Table 1. Theantibodies of the invention may be from any animal origin, includingbirds and mammals. Preferably, the antibodies are human, murine (e.g.,mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse,or chicken. Most preferably, the antibodies are human antibodies. Asused herein, “human” antibodies include antibodies having the amino acidsequence of a human immunoglobulin and include antibodies isolated fromhuman immunoglobulin libraries and xenomice or other organisms that havebeen genetically engineered to produce human antibodies. For a detaileddiscussion of a few of the technologies for producing human antibodiesand human monoclonal antibodies and protocols for producing suchantibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos.5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806;5,814,318; 5,885,793; 5,916,771; and 5,939,598; and Lonberg and Huszar,Int. Rev. Immunol. 13:65-93 (1995), which are incorporated by referenceherein in their entirety. Human antibodies or “humanized” chimericmonoclonal antibodies can be produced using techniques described hereinor otherwise known in the art. For example, methods for producingchimeric antibodies are known in the art. See, for review the followingreferences which are hereby incorporated in their entirety: Morrison,Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabillyet al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrisonet al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al.,Nature 314:268 (1985). In addition, companies such as Abgenix, Inc.(Freemont, Calif.) and Genpharm (San Jose, Calif.) can be engaged toprovide human antibodies directed against a selected antigen usingtechnology similar to that described above.

[0208] The antibodies of the present invention may be monovalent,bivalent, trivalent or multivalent. For example, monovalent scFvs can bemultimerized either chemically or by association with another protein orsubstance. An scFv that is fused to a hexahistidine tag or a Flag tagcan be multimerized using Ni-NTA agarose (Qiagen) or using anti-Flagantibodies (Stratagene, Inc.).

[0209] The antibodies of the present invention may be monospecific,bispecific, trispecific or of greater multispecificity. Multispecificantibodies may be specific for different epitopes of a BLyS polypeptide,or fragment thereof, or may be specific for both a BLyS polypeptide, orfragment thereof, and a heterologous epitope, such as a heterologouspolypeptide or solid support material. See, e.g., PCT publications WO93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J.Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681;4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol.148:1547-1553 (1992).

[0210] The antibodies of the invention (including molecules comprising,or alternatively consisting of, antibody fragments or variants thereof)may bind immunospecifically to murine BLyS (e.g., a polypeptide havingthe amino acid sequence of human BLyS (SEQ ID NOS:3228 and/or 3229) orBLyS expressed on human monocytes; murine BLyS (SEQ ID NOS:3230 and/or3231) or BLyS expressed on murine monocytes; rat BLyS (either thesoluble forms as given in SEQ ID NOS:3232, 3233, 3234 and/or 3235 or ina membrane associated form, e.g., on the surface of rat monocytes); ormonkey BLyS (e.g., the monkey BLyS polypeptides of SEQ ID NOS:3236and/or 3237, the soluble form of monkey BLyS, or BLyS expressed onmonkey monocytes), preferably the antibodies of the invention bindimmunospecifically to human BLyS. Preferably, the antibodies of theinvention bind immunospecifically to human and monkey BLyS. Alsopreferably, the antibodies of the invention bind immunospecifically tohuman BLyS and murine BLyS. More preferably, antibodies of theinvention, bind immunospecifically and with higher affinity to humanBLyS than to murine BLyS.

[0211] Antibodies of the present invention may also be described orspecified in terms of their cross-reactivity. Antibodies that do notbind any other analog, ortholog, or homolog of a polypeptide of thepresent invention are included. Antibodies that bind polypeptides withat least 95%, at least 90%, at least 85%, at least 80%, at least 75%, atleast 70%, at least 65%, at least 60%, at least 55%, and at least 50%identity (as calculated using methods known in the art and describedherein) to a polypeptide of the present invention are also included inthe present invention. In a specific embodiment, antibodies of thepresent invention cross react with APRIL (SEQ ID NO:3239; GenBankAccession No. AF046888; J. Exp. Med. 188(6):1185-1190; PCT InternationalPublication WO97/33902). In specific embodiments, antibodies of thepresent invention cross-react with murine, rat and/or rabbit homologs ofhuman proteins and the corresponding epitopes thereof. Antibodies thatdo not bind polypeptides with less than 95%, less than 90%, less than85%, less than 80%, less than 75%, less than 70%, less than 65%, lessthan 60%, less than 55%, and less than 50% identity (as calculated usingmethods known in the art and described herein) to a polypeptide of thepresent invention are also included in the present invention. In aspecific embodiment, the above-described cross-reactivity is withrespect to any single specific antigenic or immunogenic polypeptide, orcombination(s) of 2, 3, 4, 5, or more of the specific antigenic and/orimmunogenic polypeptides disclosed herein. Further included in thepresent invention are antibodies which bind polypeptides encoded bypolynucleotides which hybridize to a polynucleotide of the presentinvention under hybridization conditions (as described herein).

[0212] In preferred embodiments, the antibodies of the present invention(including molecules comprising, or alternatively consisting of,antibody fragments or variants thereof), immunospecifically bind to BLySand do not cross-react with any other antigens. In more preferredembodiments, the antibodies of the invention immunopecifically bind toBLyS and do not cross-react with TRAIL, APRIL, Endokine-alpha,TNF-alpha, TNF-beta, Fas-L or LIGHT.

[0213] The present invention also provides for a nucleic acid molecule,generally

[0214] isolated, encoding an antibody of the invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof). In one embodiment, a nucleic acid molecule of theinvention encodes an antibody comprising, or alternatively consistingof, a VH domain having an amino acid sequence of any one of the VHdomains referred to in Table 1. In another embodiment, a nucleic acidmolecule of the present invention encodes an antibody comprising, oralternatively consisting of, a VH CDR1 having an amino acid sequence ofany one of the VH CDR1s referred to in Table 1. In another embodiment, anucleic acid molecule of the present invention encodes an antibodycomprising, or alternatively consisting of, a VH CDR2 having an aminoacid sequence of any one of the VH CDR2s referred to in Table 1. In yetanother embodiment, a nucleic acid molecule of the present inventionencodes an antibody comprising, or alternatively consisting of, a VHCDR3 having an amino acid sequence of any one of the VH CDR3s referredto in Table 1. Nucleic acid molecules encoding antibodies thatimmunospecifically bind BLyS and comprise, or alternatively consist of,fragments or variants of the VH domains and/or VH CDRs are alsoencompassed by the invention.

[0215] In another embodiment, a nucleic acid molecule of the inventionencodes an antibody (including molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof), comprising, oralternatively consisting of, a VL domain having an amino acid sequenceof any one of the VL domains referred to in Table 1. In anotherembodiment, a nucleic acid molecule of the present invention encodes anantibody comprising, or alternatively consisting of, a VL CDR1 havingamino acid sequence of any one of the VL CDR1s referred to in Table 1.In another embodiment, a nucleic acid molecule of the present inventionencodes an antibody comprising, or alternatively consisting of, a VLCDR2 having an amino acid sequence of any one of the VL CDR2s referredto in Table 1. In yet another embodiment, a nucleic acid molecule of thepresent invention encodes an antibody comprising, or alternativelyconsisting of, a VL CDR3 having an amino acid sequence of any one of theVL CDR3s referred to in Table 1. Nucleic acid encoding antibodies thatimmunospecifically bind BLyS and comprise, or alternatively consist of,fragments or variants of the VL domains and/or VLCDR(s) are alsoencompassed by the invention.

[0216] In another embodiment, a nucleic acid molecule of the inventionencodes an antibody (including molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof), comprising, oralternatively consisting of, a VH domain having an amino acid sequenceof any one of the VH domains referred to in Table 1 and a VL domainhaving an amino acid sequence of any one of the VL domains referred toin Table 1. In another embodiment, a nucleic acid molecule of theinvention encodes an antibody comprising, or alternatively consistingof, a VH CDR1, a VL CDR1, a VH CDR2, a VL CDR2, a VH CDR3, a VL CDR3, orany combination thereof having an amino acid sequence referred to inTable 1. Nucleic acid encoding antibodies that immunospecifically bindBLyS and comprise, or alternatively consist of, fragments or variants ofthe VL and/or domains and/or VHCDR(s) and/or VLCDR(s) are alsoencompassed by the invention.

[0217] The present invention also provides antibodies that comprise, oralternatively consist of, variants (including derivatives) of the VHdomains, VH CDRs, VL domains, and VL CDRs described herein, whichantibodies immunospecifically bind to BLyS. Standard techniques known tothose of skill in the art can be used to introduce mutations in thenucleotide sequence encoding a molecule of the invention, including, forexample, site-directed mutagenesis and PCR-mediated mutagenesis whichresult in amino acid substitutions. Preferably, the variants (includingderivatives) encode less than 50 amino acid substitutions, less than 40amino acid subsitutions, less than 30 amino acid substitutions, lessthan 25 amino acid substitutions, less than 20 amino acid substitutions,less than 15 amino acid substitutions, less than 10 amino acidsubstitutions, less than 5 amino acid substitutions, less than 4 aminoacid substitutions, less than 3 amino acid substitutions, or less than 2amino acid substitutions relative to the reference VH domain, VHCDR1,VHCDR2, VHCDR3, VL domain, VLCDR1, VLCDR2, or VLCDR3. In specificembodiments, the variants encode substitutions of VHCDR3. In a preferredembodiment, the variants have conservative amino acid substitutions atone or more predicted non-essential amino acid residues. A “conservativeamino acid substitution” is one in which the amino acid residue isreplaced with an amino acid residue having a side chain with a similarcharge. Families of amino acid residues having side chains with similarcharges have been defined in the art. These families include amino acidswith basic side chains (e.g., lysine, arginine, histidine), acidic sidechains (e.g. aspartic acid, glutamic acid), uncharged polar side chains(e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine,cysteine), nonpolar side chains (e.g., alanine, valine, leucine,isoleucine, proline, phenylalanine, methionine, tryptophan),beta-branched side chains (e.g., threonine, valine, isoleucine) andaromatic side chains (e.g., tyrosine, phenylalanine, tryptophan,histidine). Alternatively, mutations can be introduced randomly alongall or part of the coding sequence, such as by saturation mutagenesis,and the resultant mutants can be screened for biological activity toidentify mutants that retain activity (e.g., the ability to bind BLyS).Following mutagenesis, the encoded protein may routinely be expressedand the functional and/or biological activity of the encoded protein,(e.g., ability to immunospecifically bind BLyS) can be determined usingtechniques described herein or by routinely modifying techniques knownin the art.

[0218] The antibodies of the invention include derivatives (i.e.,variants) that are modified, e.g., by the covalent attachment of anytype of molecule to the antibody such that covalent attachment does notaffect the ability of the antibody to immunospecifically bind to BLyS.For example, but not by way of limitation, derivatives of the inventioninclude antibodies that have been modified, e.g., by glycosylation,acetylation, pegylation, phosphorylation, amidation, derivatization byknown protecting/blocking groups, proteolytic cleavage, linkage to acellular ligand or other protein, etc. Any of numerous chemicalmodifications may be carried out by known techniques, including, but notlimited to, specific chemical cleavage, acetylation, formylation,metabolic synthesis of tunicamycin, etc. Additionally, the derivativemay contain one or more non-classical amino acids.

[0219] In a specific embodiment, an antibody of the invention (includinga molecule comprising, or alternatively consisting of, an antibodyfragment or variant thereof), that immunospecifically binds BLyS,comprises, or alternatively consists of, an amino acid sequence encodedby a nucleotide sequence that hybridizes to a nucleotide sequence thatis complementary to that encoding one of the VH or VL domains referredto in Table 1 under stringent conditions, e.g., hybridization tofilter-bound DNA in 6×sodium chloride/sodium citrate (SSC) at about 45°C. followed by one or more washes in 0.2×SSC/0.1% SDS at about 50-65°C., under highly stringent conditions, e.g., hybridization tofilter-bound nucleic acid in 6×SSC at about 45° C. followed by one ormore washes in 0.1×SSC/0.2% SDS at about 68° C., or under otherstringent hybridization conditions which are known to those of skill inthe art (see, for example, Ausubel, F. M. et al., eds., 1989, CurrentProtocols in Molecular Biology, Vol. I, Green Publishing Associates,Inc. and John Wiley & Sons, Inc., New York at pages 6.3.1-6.3.6 and2.10.3). In another embodiment, an antibody of the invention thatimmunospecifically binds to BLyS, comprises, or alternatively consistsof, an amino acid sequence encoded by a nucleotide sequence thathybridizes to a nucleotide sequence that is complementary to thatencoding one of the VH CDRs or VL CDRs referred to in Table 1 understringent conditions, e.g., hybridization under conditions as describedabove, or under other stringent hybridization conditions which are knownto those of skill in the art. In another embodiment, an antibody of theinvention that immunospecifically binds to BLyS, comprises, oralternatively consists of, an amino acid sequence encoded by anucleotide sequence that hybridizes to a nucleotide sequence that iscomplementary to that encoding one of the VH CDR3s referred to in Table1 under stringent conditions e.g., hybridization under conditions asdescribed above, or under other stringent hybridization conditions whichare known to those of skill in the art. Nucleic acid molecules encodingthese antibodies are also encompassed by the invention.

[0220] In another embodiment, an antibody (including a moleculecomprising, or alternatively consisting of, an antibody fragment orvariant thereof), that immunospecifically binds to BLyS comprises, oralternatively consists of, a polypeptide having an amino acid sequencethat is at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95%, or at least 99%identical, to any one of the VH domains referred to in Table 1. Inanother embodiment, an antibody of the invention that immunospecificallybinds to BLyS comprises, or alternatively consists of, a polypeptidehaving an amino acid sequence that is at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, or at least 99% identical, to any one of the VH CDRs referredto in Table 1. In another embodiment, an antibody of the invention thatimmunospecifically binds to BLyS comprises, or alternatively consistsof, a polypeptide having an amino acid sequence that is at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 99% identical to any one of the VHCDR3s referred to in Table 1. Nucleic acid molecules encoding theseantibodies are also encompassed by the invention.

[0221] In another embodiment, an antibody of the invention (including amolecule comprising, or alternatively consisting of, an antibodyfragment or variant thereof), that immunospecifically binds to BLyScomprises, or alternatively consists of, a polypeptide having an aminoacid sequence that is at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least99% identical, to any one of the VL domains referred to in Table 1. Inanother embodiment, an antibody of the invention that immunospecificallybinds to BLyS comprises, or alternatively consists of, a polypeptidehaving an amino acid sequence that is at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, or at least 99% identical, to any one of the VL CDRs referredto in Table 1. In another embodiment, an antibody of the invention thatimmunospecifically binds to BLyS comprises, or alternatively consistsof, a polypeptide having an amino acid sequence that is at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 99% identical, to any one of the VLCDR3s referred to in Table 1. Nucleic acid molecules encoding theseantibodies are also encompassed by the invention.

[0222] Antibodies of the present invention (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) may also be described or specified in terms of theirbinding affinity for to BLyS polypeptides or fragments or variants ofBLyS polypeptides (e.g., to the soluble form of BLyS and/ormembrane-bound form of BLyS). In specific embodiments, antibodies of theinvention bind BLyS polypeptides, or fragments or variants thereof, witha dissociation constant or K_(D) of less than or equal to 5×10⁻² M, 10⁻²M, 5×10⁻³ M, 10⁻³ M, 5×10⁻⁴ M, 10⁻⁴ M, 5×10⁻⁵ M, or 10⁻⁵ M. Morepreferably, antibodies of the invention bind BLyS polypeptides orfragments or variants thereof with a dissociation constant or K_(D) lessthan or equal to 5×10⁻⁶ M, 10⁻⁶ M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, or 10⁻⁸M. Even more preferably, antibodies of the invention bind BLySpolypeptides or fragments or variants thereof with a dissociationconstant or K_(D) less than or equal to 5×10⁻⁹ M, 10⁻⁹ M, 5×10⁻¹⁰ M,10⁻¹⁰ M, 5×10⁻¹¹ M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻¹² M, 5×10⁻¹³ M, 10^(−13 M,)5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, or 10⁻¹⁵ M. The invention encompassesantibodies that bind BLyS polypeptides with a dissociation constant orK_(D) that is within any one of the ranges that are between each of theindividual recited values.

[0223] In specific embodiments, antibodies of the invention bind BLySpolypeptides or fragments or variants thereof with an off rate (k_(off))of less than or equal to 5×10⁻² sec⁻¹, 10⁻² sec⁻¹, 5×10⁻³ sec⁻¹ or 10⁻³sec⁻¹. More preferably, antibodies of the invention bind BLySpolypeptides or fragments or variants thereof with an off rate (k_(off))less than or equal to 5×10⁻⁴ sec⁻¹, 10⁻⁴ sec⁻¹, 5×10⁻⁵ sec⁻¹, or 10⁻⁵sec⁻¹ 5×10⁻⁶ sec⁻¹, 10⁻⁶ sec⁻¹, 5×10⁻⁷ sec⁻¹ or 10⁻⁷ sec⁻¹. Theinvention encompasses antibodies that bind BLyS polypeptides with an offrate (k_(off)) that is within any one of the ranges that are betweeneach of the individual recited values.

[0224] In other embodiments, antibodies of the invention bind BLySpolypeptides or fragments or variants thereof with an on rate (k_(on))of greater than or equal to 10³ M⁻¹ sec⁻¹, 5×10³ M⁻¹ sec⁻¹, 10⁴ M⁻¹sec⁻¹ or 5×10⁴ M⁻¹ sec⁻¹. More preferably, antibodies of the inventionbind BLyS polypeptides or fragments or variants thereof with an on rate(k_(on)) greater than or equal to 10⁵ M−1 sec⁻¹, 5×10⁵ M⁻¹ sec⁻¹, 10⁶M⁻¹ sec⁻¹, or 5×10⁶ M⁻¹ sec⁻¹ or 10⁷ M⁻¹ sec⁻¹. The inventionencompasses antibodies that bind BLyS polypeptides with on rate (k_(on))that is within any one of the ranges that are between each of theindividual recited values.

[0225] The invention also encompasses antibodies (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) that have one or more of the same biologicalcharacteristics as one or more of the antibodies described herein. By“biological characteristics” is meant, the in vitro or in vivoactivities or properties of the antibodies, such as, for example, theability to bind to BLyS (e.g., the soluble form of BLyS, themembrane-bound form of BLyS, the soluble form and membrane-bound form ofBLyS), and/or an antigenic and/or epitope region of BLyS), the abilityto substantially block BLyS/BLyS receptor (e.g., TACI—GenBank accessionnumber AAC51790 and/or BCMA—GenBank accession number NP_(—)001183)binding, or the ability to block BLyS mediated biological activity(e.g., stimulation of B cell proliferation and immunoglobulinproduction). Optionally, the antibodies of the invention will bind tothe same epitope as at least one of the antibodies specifically referredto herein. Such epitope binding can be routinely determined using assaysknown in the art.

[0226] The present invention also provides for antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof), that neutralize BLyS or a fragment thereof, saidantibodies comprising, or alternatively consisting of, a portion (i.e.,a VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, orVL CDR3) of an scFv referred to in Table 1, more preferably having anamino acid sequence contained in SEQ ID NOS:834-872, 1570-1595, or1886-1908, and even more preferably having an amino acid sequencecontained in SEQ ID NOS:1-46, 321-329, 1563-1569, or 1881-1885 asdisclosed in Table 1, or a fragment or variant thereof. By an antibodythat “neutralizes BLyS or a fragment thereof” is meant an antibody thatdiminishes or abolishes the ability of BLyS to bind to its receptor(e.g., TACI and BCMA) to stimulate B cell proliferation, to stimulateimmunoglobulin secretion by B cells, and/or to stimulate the BLySreceptor signalling cascade. In one embodiment, an antibody thatneutralizes BLyS or a fragment thereof, comprises, or alternativelyconsists of, a polypeptide having the amino acid sequence of a VH domaincontained in SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908as disclosed in Table 1, or a fragment or variant thereof. In anotherembodiment, an antibody that neutralizes BLyS or a fragment thereof,comprises, or alternatively consists of, a polypeptide having the aminoacid sequence of a VL domain contained in SEQ ID NOS:1-46, 321-329,834-872, 1563-1595, or 1881-1908 as disclosed in Table 1, or a fragmentor variant thereof. In another embodiment, an antibody that neutralizesBLyS or a fragment thereof, comprises, or alternatively consists of, apolypeptide having the amino acid sequence of a VH CDR domain in SEQ IDNOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908 as disclosed inTable 1, or a fragment or variant thereof. In a preferred embodiment, anantibody that neutralizes BLyS or a fragment thereof, comprises, oralternatively consists of, a polypeptide having the amino acid sequenceof a VH CDR3 contained in SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595,or 1881-1908 as disclosed in Table 1, or a fragment or variant thereof.In another embodiment, an antibody that neutralizes BLyS or a fragmentthereof, comprises, or alternatively consists of, a polypeptide havingthe amino acid sequence of a VL CDR domain contained in SEQ ID NOS:1-46,321-329, 834-872, 1563-1595, or 1881-1908 as disclosed in Table 1, or afragment or variant thereof. In another preferred embodiment, anantibody that neutralizes BLyS or a fragment thereof, comprises, oralternatively consists of, a polypeptide having the amino acid sequenceof a VL CDR3 contained in SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595,or 1881-1908 as disclosed in Table 1, or a fragment or variant thereof.Nucleic acid molecules encoding these antibodies are also encompassed bythe invention.

[0227] The present invention also provides for antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof), that inhibit (i.e., diminish or abolish) BLySmediated B cell proliferation as determined by any method known in theart such as, for example, the assays described in Examples 21 and 22,infra, said antibodies comprising, or alternatively consisting of, aportion (e.g., a VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VLCDR1, VL CDR2, or VL CDR3) of an scFv having an amino acid sequence SEQID NOS:834-872, 1570-1595, 1886-1908, and even more preferably having anamino acid sequence SEQ ID NOS:1-46, 321-329, 1563-1569, 1881-1885 asdisclosed in Table 1 or a fragment or variant thereof. In oneembodiment, an antibody that inhibits BLyS mediated B cellproliferation, comprises, or alternatively consists of, a polypeptidehaving the amino acid sequence of a VH domain contained in SEQ IDNOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908, as disclosed inTable 1, or a fragment or variant thereof. In another embodiment, anantibody that inhibits BLyS mediated B cell proliferation, comprises, oralternatively consists of, a polypeptide having the amino acid sequenceof a VL domain contained in SEQ ID NOS:1-46, 321-329, 834-872,1563-1595, or 1881-1908 as disclosed in Table 1, or a fragment orvariant thereof. In a preferred embodiment, an antibody that inhibitsBLyS mediated B cell proliferation, comprises, or alternatively consistsof, a polypeptide having the amino acid sequence of a VH CDR3 containedin SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908 asdisclosed in Table 1, or a fragment or variant thereof. In anotherpreferred embodiment, an antibody that inhibits BLyS mediated B cellproliferation, comprises, or alternatively consists of, a polypeptidehaving the amino acid sequence of a VL CDR3 contained SEQ ID NOS:1-46,321-329, 834-872, 1563-1595, or 1881-1908 as disclosed in Table 1, or afragment or variant thereof. Nucleic acid molecules encoding theseantibodies are also encompassed by the invention.

[0228] The present invention also provides for antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof), that enhance the activity of BLyS or a fragmentthereof, said antibodies comprising, or alternatively consisting of, aportion (i.e., a VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VLCDR1, VL CDR2, or VL CDR3) of an scFv having an amino acid sequence SEQID NOS:834-872, 1570-1595, or 1886-1908, and preferably having an aminoacid sequence of SEQ ID NOS:1-46, 321-329, 1563-1569, or 1881-1885, asdisclosed in Table 1, or a fragment or variant thereof. By an antibodythat “enhances the activity of BLyS or a fragment thereof” is meant anantibody increases the ability of BLyS to bind to its receptor (e.g.,TACI or BCMA), to stimulate B cell proliferation, to stimulateimmunoglobulin secretion by B cells, and/or to stimulate the BLySreceptor signalling cascade. In one embodiment, an antibody thatenhances the activity of BLyS or a fragment thereof, comprises, oralternatively consists of, a polypeptide having the amino acid sequenceof a VH domain contained in SEQ ID NOS:1-46, 321-329, 834-872,1563-1595, or 1881-1908 as disclosed in Table 1, or a fragment orvariant thereof. In another embodiment, an antibody that enhances theactivity of BLyS or a fragment thereof, comprises, or alternativelyconsists of, a polypeptide having the amino acid sequence of a VL domaincontained in SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908as disclosed in Table 1, or a fragment or variant thereof. In anotherembodiment, an antibody that enhances the activity of BLyS or a fragmentthereof, comprises, or alternatively consists of, a polypeptide havingthe amino acid sequence of a VH CDR domain contained in SEQ ID NOS:1-46,321-329, 834-872, 1563-1595, or 1881-1908 as disclosed in Table 1, or afragment or variant thereof. In a preferred embodiment, an antibody thatenhances the activity of BLyS or a fragment thereof, comprises, oralternatively consists of, a polypeptide having the amino acid sequenceof a VH CDR3 contained in SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595,or 1881-1908 as disclosed in Table 1, or a fragment or variant thereof.In another embodiment, an antibody that enhances BLyS or a fragmentthereof, comprises, or alternatively consists of, a polypeptide havingthe amino acid sequence of a VL CDR domain contained in SEQ ID NOS:1-46,321-329, 834-872, 1563-1595, or 1881-1908 as disclosed in Table 1, or afragment or variant thereof. In another preferred embodiment, anantibody that enhances the activity of BLyS or a fragment thereof,comprises, or alternatively consists of, a polypeptide having the aminoacid sequence of a VL CDR3 contained in SEQ ID NOS:1-46, 321-329,834-872, 1563-1595, or 1881-1908 as disclosed in Table 1, or a fragmentor variant thereof. Nucleic acid molecules encoding these antibodies arealso encompassed by the invention.

[0229] The present invention also provides for antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof), that stimulate BLyS mediated B cell proliferationas determined by any method known in the art, such as, for example, theassays described in Examples 21 and 22, infra, said antibodiescomprising, or alternatively consisting of, a portion (e.g., a VHdomain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, or VLCDR3) of an scFv having an amino acid sequence of SEQ ID NOS:834-872,1570-1595, or 1886-1908, and even more preferably having an amino acidsequence of SEQ ID NOS:1-46, 321-329, 1563-1569, or 1881-1885 asdisclosed in Table 1 or a fragment or variant thereof. In oneembodiment, an antibody that stimulates BLyS mediated B cellproliferation, comprises, or alternatively consists of, a polypeptidehaving the amino acid sequence of a VH domain contained in SEQ IDNOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908 as disclosed inTable 1, or a fragment or variant thereof. In another embodiment, anantibody that stimulates BLyS mediated B cell proliferation, comprises,or alternatively consists of, a polypeptide having the amino acidsequence of a VL domain contained in SEQ ID NOS:1-46, 321-329, 834-872,1563-1595, or 1881-1908 as disclosed in Table 1, or a fragment orvariant thereof. In a preferred embodiment, an antibody that stimulatesBLyS mediated B cell proliferation, comprises, or alternatively consistsof, a polypeptide having the amino acid sequence of a VH CDR3 containedin SEQ ID NOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908 asdisclosed in Table 1, or a fragment or variant thereof. In anotherpreferred embodiment, an antibody that stimulates BLyS mediated B cellproliferation, comprises, or alternatively consists of, a polypeptidehaving the amino acid sequence of a VL CDR3 contained in SEQ IDNOS:1-46, 321-329, 834-872, 1563-1595, or 1881-1908 as disclosed inTable 1, or a fragment or variant thereof. Nucleic acid moleculesencoding these antibodies are also encompassed by the invention.

[0230] The present invention also provides for fusion proteinscomprising, or alternatively consisting of, an antibody (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof), that immunospecifically binds to BLyS, and aheterologous polypeptide. Preferably, the heterologous polypeptide towhich the antibody is fused to is useful for B-cell function or isuseful to target the antibody to B-cells. In an alternative preferredembodiment, the heterologous polypeptide to which the antibody is fusedto is useful for monocyte cell function or is useful to target theantibody to a monocyte. In another embodiment, the heterologouspolypeptide to which the antibody is fused is albumin (including but notlimited to recombinant human serum albumin or fragments or variantsthereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EPPatent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998,herein incorporated by reference in their entirety)). In a preferredembodiment, antibodies of the present invention (including fragments orvariants thereof) are fused with the mature form of human serum albumin(i.e., amino acids 1-585 of human serum albumin as shown in FIGS. 1 and2 of EP Patent 0 322 094) which is herein incorporated by reference inits entirety. In another preferred embodiment, antibodies of the presentinvention (including fragments or variants thereof) are fused withpolypeptide fragments comprising, or alternatively consisting of, aminoacid residues 1-x of human serum albumin, where x is an integer from 1to 585 and the albumin fragment has human serum albumin activity. Inanother preferred embodiment, antibodies of the present invention(including fragments or variants thereof) are fused with polypeptidefragments comprising, or alternatively consisting of, amino acidresidues 1-z of human serum albumin, where z is an integer from 369 to419, as described in U.S. Pat. No. 5,766,883 herein incorporated byreference in its entirety. Antibodies of the present invention(including fragments or variants thereof) may be fused to either the N-or C-terminal end of the heterologous protein (e.g., immunoglobulin Fcpolypeptide or human serum albumin polypeptide).

[0231] In one embodiment, a fusion protein of the invention comprises,or alternatively consists of, a polypeptide having the amino acidsequence of any one or more of the VH domains referred to in Table 1 orthe amino acid sequence of any one or more of the VL domains referred toin Table 1 or fragments or variants thereof, and a heterologouspolypeptide sequence. In another embodiment, a fusion protein of thepresent invention comprises, or alternatively consists of, a polypeptidehaving the amino acid sequence of any one, two, three, or more of the VHCDRs referred to in Table 1, or the amino acid sequence of any one, two,three, or more of the VL CDRs referred to in Table 1, or fragments orvariants thereof, and a heterologous polypeptide sequence. In apreferred embodiment, the fusion protein comprises, or alternativelyconsists of, a polypeptide having the amino acid sequence of, a VH CDR3referred to in Table 1, or fragment or variant thereof, and aheterologous polypeptide sequence, which fusion proteinimmunospecifically binds to BLyS. In another embodiment, a fusionprotein comprises, or alternatively consists of a polypeptide having theamino acid sequence of at least one VH domain referred to in Table 1 andthe amino acid sequence of at least one VL domain referred to in Table 1or fragments or variants thereof, and a heterologous polypeptidesequence. Preferably, the VH and VL domains of the fusion proteincorrespond to the same scFv referred to in Table 1. In yet anotherembodiment, a fusion protein of the invention comprises, oralternatively consists of a polypeptide having the amino acid sequenceof any one, two, three or more of the VH CDRs referred to in Table 1 andthe amino acid sequence of any one, two, three or more of the VL CDRsreferred to in Table 1, or fragments or variants thereof, and aheterologous polypeptide sequence. Preferably, two, three, four, five,six, or more of the VHCDR(s) or VLCDR(s) correspond to the same scFvreferred to in Table 1. Nucleic acid molecules encoding these fusionproteins are also encompassed by the invention.

[0232] The present invention also provides: antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof), that immunospecifically bind to the soluble formof BLyS; antibodies that immunospecifically bind to the membrane-boundform of BLyS; and antibodies that immunospecifically bind to both thesoluble form and membrane-bound form of BLyS.

[0233] In one embodiment of the present invention, antibodies (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to the soluble form ofBLyS, comprise, or alternatively consist of, a polypeptide having theamino acid sequence of any one or more of the VH domains contained inSEQ ID NOS:1563-1880 as disclosed in Table 1 and/or the amino acidsequence of any one or more of the VL domains contained in SEQ ID NOS:1563-1880 as disclosed in Table 1, or fragment(s) or variant(s)(including derivative) thereof. Preferably, the VH and VL domains of theantibody correspond to the same scFv as disclosed in Table 1. In anotherembodiment, antibodies that immunospecifically bind to the soluble formof BLyS are provided that comprise, or alternatively consist of, apolypeptide having the amino acid sequence of any one, two, three, ormore of the VH CDRs contained SEQ ID NOS: 1563-1880 as disclosed inTable 1 and/or the amino acid sequence of any one, two, three, or moreof the VL CDRs contained in SEQ ID NOS: 1563-1880 as disclosed in Table1, or fragment(s) or variant(s) thereof. Preferably, two, three, four,five, six or more of the VH and VL CDRs of the antibody correspond tothe same scFv as disclosed in Table 1. In a preferred embodiment,antibodies that immunospecifically bind to the soluble form of BLyS areprovided that comprise, or alternatively consist of, a polypeptidehaving the amino acid sequence of any one or more of the VH CDR3scontained in SEQ ID NOS: 1563-1880 as disclosed in Table 1 and/or theamino acid sequence of any one or more of the VL CDR3s contained in SEQID NOS: 1563-1880 as disclosed in Table 1, or fragment(s) or variant(s)thereof. Preferably, the VHCDR3 and VLCDR3 of the antibody correspond tothe same scFv, as disclosed in Table 1. Nucleic acid molecules encodingthese antibodies are also encompassed by the invention.

[0234] In another embodiment of the present invention, antibodies(including molecules comprising, or alternatively consisting of,antibody fragments or variants thereof) that immunospecifically bind tothe membrane-bound form of BLyS are provided that comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof any one or more of the VH domains contained in SEQ ID NOS: 1881-2128as disclosed in Table 1 and/or the amino acid sequence of any one ormore of the VL domains contained in SEQ ID NOS: 1881-2128 as disclosedin Table 1, or a fragment or variant thereof. Preferably, the VH and VLdomains of the antibody correspond to the same scFv as disclosed inTable 1. In another embodiment, antibodies that immunospecifically bindto the membrane-bound form of BLyS are provided that comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof any one, two, three, or more of the VH CDRs contained in SEQ ID NOS:1881-2128 as disclosed in Table 1 and/or the amino acid sequence of anyone, two, three, or more of the VL CDRs contained in SEQ ID NOS:1881-2128 as disclosed in Table 1, or fragrnent(s) or variant(s)thereof. Preferably, two, three, four, five, six or more of the VH andVL CDRs of the antibody correspond to the same scFv as disclosed inTable 1. In a preferred embodiment, antibodies that immunospecificallybind to the membrane-bound form of BLyS are provided that comprise, oralternatively consist of, a polypeptide having the amino acid sequenceof any one or more of the VH CDR3s contained in SEQ ID NOS: 1881-2128 asdisclosed in Table 1 and/or the amino acid sequence of any one or moreof the VL CDR3s contained in SEQ ID NOS: 1881-2128 as disclosed in Table1, or fragment(s) or variant(s) thereof. Preferably, the VHCDR3 andVLCDR3 of the antibody correspond to the same scFv, as disclosed inTable 1. Nucleic acid molecules encoding these antibodies are alsoencompassed by the invention.

[0235] In another embodiment of the present invention, antibodies(including molecules comprising, or alternatively consisting of,antibody fragments or variants thereof) that immunospecifically bind tothe soluble form and membrane-bound form of BLyS, are provided thatcomprise, or alternatively consist of, a polypeptide having the aminoacid sequence of any one or more of the VH domains contained in SEQ IDNOS: 1-1562 as disclosed in Table 1 and/or the amino acid sequence ofany one or more of the VL domains contained in SEQ ID NOS: 1-1562 asdisclosed in Table 1, or a fragment or variant thereof. Preferably, theVH and VL domains of the antibody correspond to the same scFv asdisclosed in Table 1. In another embodiment, antibodies thatimmunospecifically bind to the soluble form and membrane-bound form ofBLyS are provided that comprise, or alternatively consist of, apolypeptide having the amino acid sequence of any one, two, three, ormore of the VH CDRs contained in SEQ ID NOS: 1-1562 as disclosed inTable 1 and/or the amino acid sequence of any one, two, three, or moreof the VL CDRs contained in SEQ ID NOS: 1-1562 as disclosed in Table 1,or fragment(s) or variant(s) thereof. Preferably, two, three, four,five, six or more of the VH and VL CDRs of the antibody correspond tothe same scFv as disclosed in Table 1. In a preferred embodiment,antibodies that immunospecifically bind to the soluble form andmembrane-bound form of BLyS are provided that comprise, or alternativelyconsist of, a polypeptide having the amino acid sequence of any one ormore of the VH CDR3s contained in SEQ ID NOS: 1-1562, disclosed in Table1 and/or the amino acid sequence of any one or more of the VL CDR3scontained in SEQ ID NOS: 1-1562, disclosed in Table 1, or fragment(s) orvariant(s) thereof. Preferably, the VHCDR3 and VLCDR3 of the antibodycorrespond to the same scFv, as disclosed in Table 1.

[0236] The present invention also provides for mixtures of antibodies(including scFvs and other molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof) thatimmunospecifically bind to BLyS, wherein the mixture has at least one,two, three, four, five or more different antibodies of the invention. Inparticular, the invention provides for mixtures of different antibodiesthat immunospecifically bind to the soluble form of BLyS, themembrane-bound form of BLyS, and/or both the membrane-bound form andsoluble form of BLyS. In specific embodiments, the invention providesmixtures of at least 2, preferably at least 4, at least 6, at least 8,at least 10, at least 12, at least 15, at least 20, or at least 25different antibodies that immunospecifically bind to BLyS, wherein atleast 1, at least 2, at least 4, at least 6, or at least 10, antibodiesof the mixture is an antibody of the invention. In a specificembodiment, each antibody of the mixture is an antibody of theinvention.

[0237] The present invention also provides for panels of antibodies(including scFvs and other molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof) thatimmunospecifically bind to BLyS, wherein the panel has at least one,two, three, four, five or more different antibodies of the invention. Inparticular, the invention provides for panels of different antibodiesthat immunospecifically bind to the soluble form of BLyS, themembrane-bound form of BLyS, and/or both the membrane-bound form andsoluble form of BLyS. In specific embodiments, the invention providesfor panels of antibodies that have different affinities for BLyS,different specificities for BLyS, or different dissociation rates. Theinvention provides panels of at least 10, preferably at least 25, atleast 50, at least 75, at least 100, at least 125, at least 150, atleast 175, at least 200, at least 250, at least 300, at least 350, atleast 400, at least 450, at least 500, at least 550, at least 600, atleast 650, at least 700, at least 750, at least 800, at least 850, atleast 900, at least 950, or at least 1000, antibodies. Panels ofantibodies can be used, for example, in 96 well plates for assays suchas ELISAs.

[0238] The present invention further provides for compositionscomprising, one or more antibodies (including scFvs and other moleculescomprising, or alternatively consisting of antibody fragments orvariants of the invention). In one embodiment, a composition of thepresent invention comprises, one, two, three, four, five, or moreantibodies that comprise or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VH domainscontained in SEQ ID NOS:1563-1880 as disclosed in Table 1, or a variantthereof. In another embodiment, a composition of the present inventioncomprises, one, two, three, four, five, or more antibodies thatcomprise, or alternatively consist of, a polypeptide having an aminoacid sequence of any one or more of the VH CDR1s contained in SEQ IDNOS:1563-1880 as disclosed in Table 1, or a variant thereof. In anotherembodiment, a composition of the present invention comprises, one, two,three, four, five or more antibodies that comprise, or alternativelyconsist of, a polypeptide having an amino acid sequence of any one ormore of the VH CDR2s contained in SEQ ID NOS:1563-1880 as disclosed inTable 1, or a variant thereof. In a preferred embodiment, a compositionof the present invention comprises, one, two, three, four, five, or moreantibodies that comprise, or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VH CDR3scontained in SEQ ID NOS:1563-1880, as disclosed in Table 1 or a variantthereof.

[0239] The present invention further provides for compositionscomprising, one or more antibodies (including scFvs and other moleculescomprising, or alternatively consisting of antibody fragments orvariants of the invention). In one embodiment, a composition of thepresent invention comprises, one, two, three, four, five, or moreantibodies that comprise or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VH domainscontained in SEQ ID NOS:1881-2128 as disclosed in Table 1, or a variantthereof. In another embodiment, a composition of the present inventioncomprises, one, two, three, four, five, or more antibodies thatcomprise, or alternatively consist of, a polypeptide having an aminoacid sequence of any one or more of the VH CDR1s contained in SEQ IDNOS:1881-2128 as disclosed in Table 1, or a variant thereof. In anotherembodiment, a composition of the present invention comprises, one, two,three, four, five or more antibodies that comprise, or alternativelyconsist of, a polypeptide having an amino acid sequence of any one ormore of the VH CDR2s contained in SEQ ID NOS:1881-2128 as disclosed inTable 1, or a variant thereof. In a preferred embodiment, a compositionof the present invention comprises, one, two, three, four, five, or moreantibodies that comprise, or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VH CDR3scontained in SEQ ID NOS:1881-2128 as disclosed in Table 1 or a variantthereof.

[0240] The present invention further provides for compositionscomprising, one or more antibodies (including scFvs, or moleculescomprising, or alternatively consisting of antibody fragments orvariants of the invention). In one embodiment, a composition of thepresent invention comprises, one, two, three, four, five, or moreantibodies that comprise or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VH domainscontained in SEQ ID NOS:1-1562 as disclosed in Table 1, or a variantthereof. In another embodiment, a composition of the present inventioncomprises, one, two, three, four, five, or more antibodies thatcomprise, or alternatively consist of, a polypeptide having an aminoacid sequence of any one or more of the VH CDR1s contained in SEQ IDNOS:1-1562 as disclosed in Table 1, or a variant thereof. In anotherembodiment, a composition of the present invention comprises, one, two,three, four, five or more antibodies that comprise, or alternativelyconsist of, a polypeptide having an amino acid sequence of any one ormore of the VH CDR2s contained in SEQ ID NOS:1-1562 as disclosed inTable 1, or a variant thereof. In a preferred embodiment, a compositionof the present invention comprises, one, two, three, four, five, or moreantibodies that comprise, or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VH CDR3scontained in SEQ ID NOS:1-1562 as disclosed in Table 1 or a variantthereof.

[0241] Other embodiments of the present invention providing forcompositions comprising, one or more antibodies (including scFvs andother molecules comprising, or alternatively consisting of antibodyfragments or variants of the invention) are listed below. In anotherembodiment, a composition of the present invention comprises, one, two,three, four, five, or more antibodies that comprise, or alternativeconsist of, a polypeptide having an amino acid sequence of any one ormore of the VL domains contained in SEQ ID NOS:1563-1880 as disclosed inTable 1, or avariant thereof. In another embodiment, a composition ofthe present invention comprises, one, two, three, four, five, or moreantibodies that comprise, or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VL CDR1 scontained in SEQ ID NOS:1563-1880 as disclosed in Table 1, or a variantthereof. In another embodiment, a composition of the present inventioncomprises, one, two, three, four, five, or more antibodies thatcomprise, or alternatively consist of, a polypeptide having an aminoacid sequence of any one or more of the VL CDR2s contained SEQ IDNOS:1563-1880 as disclosed in Table 1, or a variant thereof. In apreferred embodiment, a composition of the present invention comprises,one, two, three, four, five, or more antibodies that comprise, oralternatively consist of, a polypeptide having an amino acid sequence ofany one or more of the VL CDR3s contained in SEQ ID NOS:1563-1880 asdisclosed in Table 1, or a variant thereof.

[0242] Other embodiments of the present invention providing forcompositions comprising, one or more antibodies (including scFvs andother molecules comprising, or alternatively consisting of antibodyfragments or variants of the invention) are listed below. In anotherembodiment, a composition of the present invention comprises, one, two,three, four, five, or more antibodies that comprise, or alternativelyconsist of, a polypeptide having an amino acid sequence of any one ormore of the VL domains contained in SEQ ID NOS:1881-2128 as disclosed inTable 1, or a variant thereof. In another embodiment, a composition ofthe present invention comprises, one, two, three, four, five, or moreantibodies that comprise, or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VL CDR1scontained in SEQ ID NOS:1881-2128 as disclosed in Table 1, or a variantthereof. In another embodiment, a composition of the present inventioncomprises, one, two, three, four, five, or more antibodies thatcomprise, or alternatively consist of, a polypeptide having an aminoacid sequence of any one or more of the VL CDR2s SEQ ID NOS:1881-2128 asdisclosed in Table 1, or a variant thereof. In a preferred embodiment, acomposition of the present invention comprises, one, two, three, four,five, or more antibodies that comprise, or alternatively consist of, apolypeptide having an amino acid sequence of any one or more of the VLCDR3s contained in SEQ ID NOS:1881-2128 as disclosed in Table 1, or avariant thereof

[0243] Other embodiments of the present invention providing forcompositions comprising, one or more antibodies (including scFvs andother molecules comprising, or alternatively consisting of antibodyfragments or variants of the invention) are listed below. In anotherembodiment, a composition of the present invention comprises, one, two,three, four, five, or more antibodies that comprise, or alternativelyconsist of, a polypeptide having an amino acid sequence of any one ormore of the VL domains contained in SEQ ID NOS:1-1562 as disclosed inTable 1, or a variant thereof. In another embodiment, a composition ofthe present invention comprises, one, two, three, four, five, or moreantibodies that comprise, or alternatively consist of, a polypeptidehaving an amino acid sequence of any one or more of the VL CDR1scontained in SEQ ID NOS:1-1562 as disclosed in Table 1, or a variantthereof. In another embodiment, a composition of the present inventioncomprises, one, two, three, four, five, or more antibodies thatcomprise, or alternatively consist of, a polypeptide having an aminoacid sequence of any one or more of the VL CDR2s SEQ ID NOS:1-1562 asdisclosed in Table 1, or a variant thereof. In a preferred embodiment, acomposition of the present invention comprises, one, two, three, four,five, or more antibodies that comprise, or alternatively consist of, apolypeptide having an amino acid sequence of any one or more of the VLCDR3s contained in SEQ ID NOS:1-1562 as disclosed in Table 1, or avariant thereof.

[0244] In a preferred embodiment, a composition of the present inventioncomprises, one, two, three, four, five, or more antibodies thatcomprise, or alternatively consist of, a polypeptide having an aminoacid sequence of any one or more of the VH domains in disclosed in Table1, or a variant thereof, and an amino acid sequence of any one or moreof the VL domains disclosed in Table 1, or a variant thereof wherein theVH and VL domains are from scFvs with the same specificity (i.e., fromscFvs that bind soluble BLyS (SEQ ID NOS:1563-1880), from scFvs thatbind membrane-bound BLyS (SEQ ID 1881-2128), or from scFvs that bindboth soluble and membrane-bound BLyS (SEQ ID NOS:1-1562). In a preferredembodiment the invention provides antibodies wherein the VH CDRX (whereX=1,2, or 3) and VL CDRY (where Y=1,2, or 3) are from scFvs with thesame specificity (i.e., from scFvs that bind soluble BLyS (SEQ IDNOS:1563-1880), from scFvs that bind membrane-bound BLyS (SEQ IDNOS:1881-2128), or from scFvs that bind both soluble and membrane-boundBLyS (SEQ ID NOS:1-1562). In yet another embodiment, a composition ofthe present invention comprises one or more fusion proteins.

[0245] As discussed in more detail below, a composition of the inventionmay be used either alone or in combination with other compositions. Theantibodies (including scFvs and other molecules comprising, oralternatively consisting of antibody fragments or variants of thepresent invention) may further be recombinantly fused to a heterologouspolypeptide at the N- or C-terminus or chemically conjugated (includingcovalently and non-covalently conjugations) to polypeptides or othercompositions. For example, antibodies of the present invention may berecombinantly fused or conjugated to molecules useful as labels indetection assays and effector molecules such as heterologouspolypeptides, drugs, radionuclides, or toxins. See, e.g., PCTpublications WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No.5,314,995; and EP 396,387.

[0246] Antibodies of the present invention (including scFvs and othermolecules comprising, or alternatively consisting of antibody fragmentsor variants of the present invention) may be used, for example, but notlimited to, to purify and detect BLyS, and to target the polypeptides ofthe present invention to cells expressing membrane-bound BLyS or BLySreceptor, including both in vitro and in vivo diagnostic and therapeuticmethods. For example, the antibodies have use in immunoassays forqualitatively and quantitatively measuring levels of BLyS in biologicalsamples. See, e.g., Harlow et al., Antibodies: A Laboratory Manual,(Cold Spring Harbor Laboratory Press, 2nd ed. 1988) (incorporated byreference herein in its entirety).

[0247] Methods Producing Antibodies

[0248] The antibodies of the invention (including scFvs and othermolecules comprising, or alternatively consisting of antibody fragmentsor variants of the invention) can be produced by any method known in theart for the synthesis of antibodies, in particular, by chemicalsynthesis or preferably, by recombinant expression techniques.

[0249] The single chain Fvs disclosed in Table 1 were generated usingphage display methods known in the art. Furthermore, other scFvs thatimmunospecifically bind BLyS may be generated using phage displaymethods known in the art. In phage display methods, functional antibodydomains are displayed on the surface of phage particles which carry thepolynucleotide sequences encoding them. In particular, DNA sequencesencoding VH and VL domains are amplified from animal cDNA libraries(e.g. human or murine cDNA libraries of lymphoid tissues) or syntheticcDNA libraries. The DNA encoding the VH and VL domains are joinedtogether by an scFv linker by PCR and cloned into a phagemid vector(e.g., p CANTAB 6 or pComb 3 HSS). The vector is electroporated in E.coli and the E. coli is infected with helper phage. Phage used in thesemethods are typically filamentous phage including fd and M13 and the VHand VL domains are usually recombinantly fused to either the phage geneIII or gene VIII. Phage expressing an antigen binding domain that bindsto an antigen of interest (i.e., BLyS or a fragment thereof) can beselected or identified with antigen, e.g., using labeled antigen orantigen bound or captured to a solid surface or bead. Examples of phagedisplay methods that can be used to make the antibodies of the presentinvention include, but are not limited to, those disclosed in Brinkmanet al., J. Immunol. Methods 182:41-50 (1995); Ames et al., J. Immunol.Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol.24:952-958 (1994); Persic et al., Gene 187 9-18 (1997); Burton et al.,Advances in Immunology 57:191-280(1994); PCT application No. PCT/GB91/O1134; PCT publications WO 90/02809; WO 91/10737; WO 92/01047; WO92/18619; WO 93/1 1236; WO 95/15982; WO 95/20401; WO97/13844; and U.S.Pat. Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908;5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225;5,658,727; 5,733,743 and 5,969,108; each of which is incorporated hereinby reference in its entirety.

[0250] As described in the above references, after phage selection, theantibody coding regions from the phage can be isolated and used togenerate whole antibodies, including human antibodies, or any otherdesired antigen binding fragment, and expressed in any desired host,including mammalian cells, insect cells, plant cells, yeast, andbacteria, e.g., as described below. Techniques to recombinantly produceFab, Fab′ and F(ab′)2 fragments can also be employed using methods knownin the art such as those disclosed in PCT publication WO 92/22324;Mullinax et al., BioTechniques 12(6):864-869 (1992); Sawai et al., AJRI34:26-34 (1995); and Better et al., Science 240:1041-1043 (1988) (saidreferences incorporated by reference in their entireties).

[0251] To generate whole antibodies, PCR primers including VH or VLnucleotide sequences, a restriction site, and a flanking sequence toprotect the restriction site can be used to amplify the VH or VLsequences in scFv clones. Utilizing cloning techniques known to those ofskill in the art, the PCR amplified VH domains can be cloned intovectors expressing a VH constant region, e.g., the human gamma 4constant region, and the PCR amplified VL domains can be cloned intovectors expressing a VL constant region, e.g., human kappa or lambdaconstant regions. Preferably, the vectors for expressing the VH or VLdomains comprise a promoter suitable to direct expression of the heavyand light chains in the chosen expression system, a secretion signal, acloning site for the immunoglobulin variable domain, immunoglobulinconstant domains, and a selection marker such as neomycin. The VH and VLdomains may also be cloned into one vector expressing the necessaryconstant regions. The heavy chain conversion vectors and light chainconversion vectors are then co-transfected into cell lines to generatestable or transient cell lines that express full-length antibodies,e.g., IgG, using techniques known to those of skill in the art.

[0252] Cell lines that express antibodies that comprise the VH and VLdomains of scFvs of the invention have been deposited with the AmericanType Culture Collection (“ATCC”) on the dates listed in Table 2 andgiven the ATCC Deposit Numbers identified in Table 2. The ATCC islocated at 10801 University Boulevard, Manassas, Va. 20110-2209, USA.The ATCC deposit was made pursuant to the terms of the Budapest Treatyon the international recognition of the deposit of microorganisms forpurposes of patent procedure. Corresponding SEQ ID ATCC Deposit ATCCDeposit Cell Line scFv NO: Number Date NSO-B11-15 1050B11-15 24 PTA-3238Mar. 27, 2001 NSO-anti-BLyS-6D08-18 I006D08 2 PTA-3239 Mar. 27, 2001NSO- anti-BLyS-116A01-60 1116A01 327 PTA-3240 Mar. 27, 2001 IO26C04KI026C04-K 1563 PTA-3241 Mar. 27, 2001 IO50A12 I050A12 12 PTA-3242 Mar.27, 2001 IO50-B11 I050B11 9 PTA-3243 Mar. 27, 2001

[0253] Accordingly, in one embodiment, the invention provides antibodiesthat comprise the VH and VL domains of scFvs of the invention.

[0254] In a preferred embodiment, an antibody of the invention is theantibody expressed by cell line NSO-B11-15.

[0255] In a preferred embodiment, an antibody of the invention is theantibody expressed by cell line NSO-anti-BLyS-6D08-18.

[0256] In a preferred embodiment, an antibody of the invention is theantibody expressed by cell line NSO-anti-BLyS-116A01-60.

[0257] In a preferred embodiment, an antibody of the invention is theantibody expressed by cell line I026C04K.

[0258] In a preferred embodiment, an antibody of the invention is theantibody expressed by cell line I050A12.

[0259] In a preferred embodiment, an antibody of the invention is theantibody expressed by cell line NSO-B11.

[0260] In other preferred embodiments, the invention provides antibodiesthat competitively inhibit binding of an antibody comprising a fragment(e.g., VH domain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, orVLCDR3) or variant of an scFv referred to in Table 1 to a BLySpolypeptide. In preferred embodiments, the invention provides antibodiesthat which reduce the binding of an antibody comprising a fragment(e.g., VH domain, VL domain, VHCDRl, VHCDR2, VHCDR3, VLCDR1, VLCDR2, orVLCDR3) or variant of an scFv referred to in Table 1 to a BLySpolypeptide by between 1% and 10% in a competitive inhibition assay. Inpreferred embodiments, the invention provides antibodies that whichreduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide bybetween 1% and 10% in a competitive inhibition assay.

[0261] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 10% and up to 20% in a competitive inhibition assay.

[0262] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 20% and up to 30% in a competitive inhibition assay.

[0263] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 30% and up to 40% in a competitive inhibition assay.

[0264] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 40% and up to 50% in a competitive inhibition assay.

[0265] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 50% and up to 60% in a competitive inhibition assay.

[0266] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 60% and up to 70% in a competitive inhibition assay.

[0267] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 70% and up to 80% in a competitive inhibition assay.

[0268] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 80% and up to 90% in a competitive inhibition assay.

[0269] In preferred embodiments, the invention provides antibodies thatwhich reduce the binding of an antibody comprising a fragment (e.g., VHdomain, VL domain, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, or VLCDR3) orvariant of an scFv referred to in Table 1 to a BLyS polypeptide by atleast 90% and up to 100% in a competitive inhibition assay.

[0270] In other preferred embodiments, the invention provides antibodiesthat competitively inhibit binding of the antibody produced by the cellline having ATCC deposit number PTA-3238 to a BLyS polypeptide.

[0271] In other preferred embodiments, the invention provides antibodiesthat competitively inhibit binding of the antibody produced by the cellline having ATCC deposit number PTA-3239 to a BLyS polypeptide.

[0272] In other preferred embodiments, the invention provides antibodiesthat competitively inhibit binding of the antibody produced by the cellline having ATCC deposit number PTA-3240 to a BLyS polypeptide.

[0273] In other preferred embodiments, the invention provides antibodiesthat competitively inhibit binding of the antibody produced by the cellline having ATCC deposit number PTA-3241 to a BLyS polypeptide.

[0274] In other preferred embodiments, the invention provides antibodiesthat competitively inhibit binding of the antibody produced by the cellline having ATCC deposit number PTA-3242 to a BLyS polypeptide.

[0275] In other preferred embodiments, the invention provides antibodiesthat competitively inhibit binding of the antibody produced by the cellline having ATCC deposit number PTA-3243 to a BLyS polypeptide.

[0276] For some uses, including in vivo use of antibodies in humans andin vitro detection assays, it may be preferable to use human or chimericantibodies. Completely human antibodies are particularly desirable fortherapeutic treatment of human patients. See also, U.S. Pat. Nos.4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433,WO 98/24893, WO98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; eachof which is incorporated herein by reference in its entirety. In aspecific embodiment, antibodies of the present invention comprise one ormore VH and VL domains corresponding to the human scFvs of the inventionand framework regions from another immunoglobulin molecule, preferably ahuman immunoglobulin molecule. In a specific embodiment, antibodies ofthe present invention comprise one or more CDRs corresponding to thehuman scFvs of the invention and framework regions from anotherimmunoglobulin molecule, preferably a human immunoglobulin molecule. Inother embodiments, an antibody of the present invention comprises one,two, three, four, five, six or more VL CDRs or VH CDRs corresponding toone or more of the human scFvs referred to in Table 1, or fragments orvariants thereof, and framework regions (and, optionally CDRs notderived from the scFvs in Table 1) from a human immunoglobulin molecule.In a preferred embodiment, an antibody of the present inventioncomprises a VH CDR3, VL CDR3, or both, corresponding to the same scFv,or different scFvs referred to in Table 1, or fragments or variantsthereof, and framework regions from a human immunoglobulin.

[0277] A chimeric antibody is a molecule in which different portions ofthe antibody are derived from different immunoglobulin molecules such asantibodies having a variable region derived from a human antibody and anon-human immunoglobulin constant region. Methods for producing chimericantibodies are known in the art. See e.g., Morrison, Science 229:1202(1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., J.Immunol. Methods 125:191-202 (1989); U.S. Pat. Nos. 5,807,715;4,816,567; and 4,816,397, which are incorporated herein by reference intheir entirety. Chimeric antibodies comprising one or more CDRs fromhuman species and framework regions from a non-human immunoglobulinmolecule (e.g., framework regions from a canine or feline immunoglobulinmolecule) can be produced using a variety of techniques known in the artincluding, for example, CDR-grafting (EP 239,400; PCT publication WO91/09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneeringor resurfacing (EP 592,106; EP 519,596; Padlan, Molecular hnmunology28(4/5):489-498 (1991); Studnicka et al., Protein Engineering7(6):805-814 (1994); Roguska et al., PNAS 91:969-973 (1994)), and chainshuffling (U.S. Pat. No. 5,565,332). In a preferred embodiment, chimericantibodies comprise a human CDR3 having an amino acid sequence of anyone of the VH CDR3s or VL CDR3s referred to in Table 1, or a variantthereof, and non-human framework regions or human framework regionsdifferent from those of the frameworks in the corresponding scFvdisclosed in Table 1. Often, framework residues in the framework regionswill be substituted with the corresponding residue from the CDR donorantibody to alter, preferably improve, antigen binding. These frameworksubstitutions are identified by methods well known in the art, e.g., bymodeling of the interactions of the CDR and framework residues toidentify framework residues important for antigen binding and sequencecomparison to identify unusual framework residues at particularpositions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmannet al., Nature 332:323 (1988), which are incorporated herein byreference in their entireties.)

[0278] Further, the antibodies of the invention can, in turn, beutilized to generate anti-idiotype antibodies that “mimic” BLySpolypeptides using techniques well known to those skilled in the art.(See, e.g., Greenspan & Bona, FASEB J. 7(5):437-444 (1993); andNissinoff, J. Immunol. 147(8):2429-2438 (1991)). For example, antibodiesof the invention which bind to BLyS and competitively inhibit thebinding of BLyS to its receptor (as determined by assays well known inthe art such as, for example, that disclosed, infra) can be used togenerate antiidiotypes that “mimic” a BLyS ligand/receptor-bindingdomain and, as a consequence, bind to and neutralize BLyS receptors(e.g., TACI, BCMA, and TR20). Such neutralizing anti-idiotypes(including molecules comprising, or alternatively consisting of,antibody fragments or variants, such as Fab fragments of suchanti-idiotypes) can be used in therapeutic regimens to neutralize BLyS.For example, such anti-idiotypic antibodies can be used to bind BLySligands/receptors, and thereby block BLyS mediated biological activity.Alternatively, anti-idiotypes that “mimic” a BLyS binding domain maybind to BLyS receptor(s) and induce BLyS receptor mediated signalling(e.g., activation of nuclear factor of activated T cells (NF-AT),nuclear factor-kappa B (NF-kappa B), and/or AP-1). Such agonisticanti-idiotypes (including agonistic Fab fragments of theseanti-idiotypes) can be used in therapeutic regimens to induce or enhanceBLyS receptor mediated signalling. For example, such anti-idiotypicantibodies can be used to bind BLyS ligands/receptors, and therebystimulate BLyS mediated biological activity (e.g., B cell proliferationand/or immunoglobulin production).

[0279] Once an antibody molecule of the invention (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) has been chemically synthesized or recombinantlyexpressed, it may be purified by any method known in the art forpurification of an immunoglobulin molecule, or more generally, a proteinmolecule, such as, for example, by chromatography (e.g., ion exchange,affinity, particularly by affinity for the specific antigen afterProtein A, and sizing column chromatography), centrifugation,differential solubility, or by any other standard technique for thepurification of proteins. Further, the antibodies of the presentinvention may be fused to heterologous polypeptide sequences describedherein or otherwise known in the art, to facilitate purification.

[0280] Polynucleotides Encoding an Antibody

[0281] The invention provides polynucleotides comprising, oralternatively consisting of, a nucleotide sequence encoding an antibodyof the invention (including molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof). The inventionalso encompasses polynucleotides that hybridize under high stringency,or alternatively, under intermediate or lower stringency hybridizationconditions, e.g., as defined supra, to polynucleotides complementary tonucleic acids having a polynucleotide sequence that encodes an antibodyof the invention or a fragment or variant thereof.

[0282] The polynucleotides may be obtained, and the nucleotide sequenceof the polynucleotides determined, by any method known in the art. Sincethe amino acid sequences of the scFv antibodies and VH domains, VLdomains and CDRs thereof, are known (as described in Table 1),nucleotide sequences encoding these antibodies can be determined usingmethods well known in the art, i.e., the nucleotide codons known toencode the particular amino acids are assembled in such a way togenerate a nucleic acid that encodes the antibody, of the invention.Such a polynucleotide encoding the antibody may be assembled fromchemically synthesized oligonucleotides (e.g., as described in Kutmeieret al., BioTechniques 17:242 (1994)), which, briefly, involves thesynthesis of overlapping oligonucleotides containing portions of thesequence encoding the antibody, annealing and ligating of thoseoligonucleotides, and then amplification of the ligated oligonucleotidesby PCR.

[0283] Alternatively, a polynucleotide encoding an antibody (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) may be generated from nucleic acid from a suitablesource. If a clone containing a nucleic acid encoding a particularantibody is not available, but the sequence of the antibody molecule isknown, a nucleic acid encoding the immunoglobulin may be chemicallysynthesized or obtained from a suitable source (e.g., an antibody cDNAlibrary, or a cDNA library generated from, or nucleic acid, preferablypoly A+ RNA, isolated from, any tissue or cells expressing the antibody,such as hybridoma cells selected to express an antibody of theinvention) by PCR amplification using synthetic primers hybridizable tothe 3′ and 5′ ends of the sequence or by cloning using anoligonucleotide probe specific for the particular gene sequence toidentify, e.g., a cDNA clone from a cDNA library that encodes theantibody. Amplified nucleic acids generated by PCR may then be clonedinto replicable cloning vectors using any method well known in the art.

[0284] Once the nucleotide sequence of the antibody (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) is determined, the nucleotide sequence of the antibodymay be manipulated using methods well known in the art for themanipulation of nucleotide sequences, e.g., recombinant DNA techniques,site directed mutagenesis, PCR, etc. (see, for example, the techniquesdescribed in Sambrook et al., 1990, Molecular Cloning, A LaboratoryManual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology,John Wiley & Sons, NY, which are both incorporated by reference hereinin their entireties), to generate antibodies having a different aminoacid sequence, for example to create amino acid substitutions,deletions, and/or insertions.

[0285] In a specific embodiment, one or more of the VH and VL domainsreferred to in Table 1, or fragments or variants thereof, is insertedwithin framework regions using recombinant DNA techniques known in theart. In a specific embodiment, one, two, three, four, five, six, or moreof the CDRs referred to in Table 1, or fragments or variants thereof, isinserted within framework regions using recombinant DNA techniques knownin the art. The framework regions may be naturally occurring orconsensus framework regions, and preferably human framework regions(see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for alisting of human framework regions, the contents of which are herebyincorporated by reference in its entirety). Preferably, thepolynucleotides generated by the combination of the framework regionsand CDRs encode an antibody (including molecules comprising, oralternatively consisting of, antibody fragments or variants thereof)that specifically binds to BLyS. Preferably, as discussed supra,polynucleotides encoding variants of antibodies or antibody fragmentshaving one or more amino acid substitutions may be made within theframework regions, and, preferably, the amino acid substitutions improvebinding of the antibody to its antigen. Additionally, such methods maybe used to make amino acid substitutions or deletions of one or morevariable region cysteine residues participating in an intrachaindisulfide bond to generate antibody molecules, or antibody fragments orvariants, lacking one or more intrachain disulfide bonds. Otheralterations to the polynucleotide are encompassed by the presentinvention and fall within the ordinary skill of the art.

[0286] Recombinant Expression of an Antibody

[0287] Recombinant expression of an antibody of the invention (includingscFvs and other molecules comprising, or alternatively consisting of,antibody fragments or variants thereof (e.g., a heavy or light chain ofan antibody of the invention or a portion thereof or a single chainantibody of the invention)), requires construction of an expressionvector(s) containing a polynucleotide that encodes the antibody. Once apolynucleotide encoding an antibody molecule (e.g., a whole antibody, aheavy or light chain of an antibody, or portion thereof (preferably, butnot necessarily, containing the heavy or light chain variable domain)),of the invention has been obtained, the vector(s) for the production ofthe antibody molecule may be produced by recombinant DNA technologyusing techniques well known in the art. Thus, methods for preparing aprotein by expressing a polynucleotide containing an antibody encodingnucleotide sequence are described herein. Methods which are well knownto those skilled in the art can be used to construct expression vectorscontaining antibody coding sequences and appropriate transcriptional andtranslational control signals. These methods include, for example, invitro recombinant DNA techniques, synthetic techniques, and in vivogenetic recombination. The invention, thus, provides replicable vectorscomprising a nucleotide sequence encoding an antibody molecule of theinvention (e.g., a whole antibody, a heavy or light chain of anantibody, a heavy or light chain variable domain of an antibody, or aportion thereof, or a heavy or light chain CDR, a single chain Fv, orfragments or variants thereof), operably linked to a promoter. Suchvectors may include the nucleotide sequence encoding the constant regionof the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCTPublication WO 89/01036; and U.S. Pat. No. 5,122,464, the contents ofeach of which are hereby incorporated by reference in its entirety) andthe variable domain of the antibody may be cloned into such a vector forexpression of the entire heavy chain, the entire light chain, or boththe entire heavy and light chains.

[0288] The expression vector(s) is(are) transferred to a host cell byconventional techniques and the transfected cells are then cultured byconventional techniques to produce an antibody of the invention. Thus,the invention includes host cells containing polynucleotide(s) encodingan antibody of the invention (e.g., whole antibody, a heavy or lightchain thereof, or portion thereof, or a single chain antibody of theinvention, or a fragment or variant thereof), operably linked to aheterologous promoter. In preferred embodiments, for the expression ofentire antibody molecules, vectors encoding both the heavy and lightchains may be co-expressed in the host cell for expression of the entireimmunoglobulin molecule, as detailed below.

[0289] A variety of host-expression vector systems may be utilized toexpress the antibody molecules of the invention. Such host-expressionsystems represent vehicles by which the coding sequences of interest maybe produced and subsequently purified, but also represent cells whichmay, when transformed or transfected with the appropriate nucleotidecoding sequences, express an antibody molecule of the invention in situ.These include, but are not limited to, microorganisms such as bacteria(e.g., E. coli, B. subtilis) transformed with recombinant bacteriophageDNA, plasmid DNA or cosmid DNA expression vectors containing antibodycoding sequences; yeast (e.g., Saccharomyces, Pichia) transformed withrecombinant yeast expression vectors containing antibody codingsequences; insect cell systems infected with recombinant virusexpression vectors (e.g., baculovirus) containing antibody codingsequences; plant cell systems infected with recombinant virus expressionvectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus,TMV) or transformed with recombinant plasmid expression vectors (e.g.,Ti plasmid) containing antibody coding sequences; or mammalian cellsystems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinantexpression constructs containing promoters derived from the genome ofmammalian cells (e.g. metallothionein promoter) or from mammalianviruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5Kpromoter). Preferably, bacterial cells such as Escherichia coli, andmore preferably, eukaryotic cells, especially for the expression ofwhole recombinant antibody molecule, are used for the expression of arecombinant antibody molecule. For example, mammalian cells such asChinese hamster ovary cells (CHO), in conjunction with a vector such asthe major intermediate early gene promoter element from humancytomegalovirus is an effective expression system for antibodies(Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2(1990)).

[0290] In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the antibodymolecule being expressed. For example, when a large quantity of such aprotein is to be produced, for the generation of pharmaceuticalcompositions of an antibody molecule, vectors which direct theexpression of high levels of fusion protein products that are readilypurified may be desirable. Such vectors include, but are not limited to,the E. coli expression vector pUR278 (Ruther et al., EMBO 1. 2:1791(1983)), in which the antibody coding sequence may be ligatedindividually into the vector in frame with the lac Z coding region sothat a fusion protein is produced; pIN vectors (Inouye & Inouye, NucleicAcids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem.24:5503-5509 (1989)); and the like. pGEX vectors may also be used toexpress foreign polypeptides as fusion proteins with glutathione5-transferase (GST). In general, such fusion proteins are soluble andcan easily be purified from lysed cells by adsorption and binding tomatrix glutathione agarose beads followed by elution in the presence offree glutathione. The pGEX vectors are designed to include thrombin orfactor Xa protease cleavage sites so that the cloned target gene productcan be released from the GST moiety.

[0291] In an insect system, Autographa californica nuclear polyhedrosisvirus (AcNPV) may be used as a vector to express foreign genes. Thevirus grows in Spodoptera frugiperda cells. Antibody coding sequencesmay be cloned individually into non-essential regions (for example, thepolyhedrin gene) of the virus and placed under control of an AcNPVpromoter (for example, the polyhedrin promoter).

[0292] In mammalian host cells, a number of viral-based expressionsystems may be utilized. In cases where an adenovirus is used as anexpression vector, the antibody coding sequence of interest may beligated to an adenovirus transcription/translation control complex,e.g., the late promoter and tripartite leader sequence. This chimericgene may then be inserted in the adenovirus genome by in vitro or invivo recombination. Insertion in a non-essential region of the viralgenome (e.g., region E1 or E3) will result in a recombinant virus thatis viable and capable of expressing the antibody molecule in infectedhosts (e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 81:355-359(1984)). Specific initiation signals may also be required for efficienttranslation of inserted antibody coding sequences. These signals includethe ATG initiation codon and adjacent sequences. Furthermore, theinitiation codon must be in phase with the reading frame of the desiredcoding sequence to ensure translation of the entire insert. Theseexogenous translational control signals and initiation codons can be ofa variety of origins, both natural and synthetic. The efficiency ofexpression may be enhanced by the inclusion of appropriate transcriptionenhancer elements, transcription terminators, etc. (see, e.g., Bittneret al., Methods in Enzymol. 153:51-544 (1987)).

[0293] In addition, a host cell strain may be chosen which modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells which possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include, but are not limited to, CHO, VERY, BHK, Hela, COS, NSO,MDCK, 293, 3T3, W138, and in particular, breast cancer cell lines suchas, for example, BT483, Hs578T, HTB2, BT2O and T47D, and normal mammarygland cell line such as, for example, CRL7O3O and HsS78Bst.

[0294] For long-term, high-yield production of recombinant proteins,stable expression is preferred. For example, cell lines which stablyexpress the antibody may be engineered. Rather than using expressionvectors which contain viral origins of replication, host cells can betransformed with DNA controlled by appropriate expression controlelements (e.g., promoter, enhancer, sequences, transcriptionterminators, polyadenylation sites, etc.), and a selectable marker.Following the introduction of the foreign DNA, engineered cells may beallowed to grow for 1-2 days in an enriched media, and then are switchedto a selective media. The selectable marker in the recombinant plasmidconfers resistance to the selection and allows cells to stably integratethe plasmid into their chromosomes and grow to form foci which in turncan be cloned and expanded into cell lines. This method mayadvantageously be used to engineer cell lines which express the antibodymolecule. Such engineered cell lines may be particularly useful inscreening and evaluation of compositions that interact directly orindirectly with the antibody molecule.

[0295] A number of selection systems may be used, including but notlimited to, the herpes simplex virus thymidine kinase (Wigler et al.,Cell 11:223 (1977)), hypoxanthineguanine phosphoribosyltransferase(Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), andadenine phosphoribosyltransferase (Lowy et al., Cell 22:8 17 (1980))genes can be employed in tk-, hgprt- or aprt- cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigleret al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl.Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance tomycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072(1981)); neo, which confers resistance to the aminoglycoside G-418(Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991);Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan,Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem.62:191-217 (1993); TIB TECH 11(5):155-2 15 (May, 1993)); and hygro,which confers resistance to hygromycin (Santerre et al., Gene 30:147(1984)). Methods commonly known in the art of recombinant DNA technologymay be routinely applied to select the desired recombinant clone, andsuch methods are described, for example, in Ausubel et al. (eds.),Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993);Kriegler, Gene Transfer and Expression, A Laboratory Manual, StocktonPress, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds),Current Protocols in Human Genetics, John Wiley & Sons, NY (1994);Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981), which areincorporated by reference herein in their entireties.

[0296] The expression levels of an antibody molecule can be increased byvector amplification (for a review, see Bebbington and Hentschel, Theuse of vectors based on gene amplification for the expression of clonedgenes in mammalian cells in DNA cloning, Vol. 3. (Academic Press, NewYork, 1987)). When a marker in the vector system expressing antibody isamplifiable, increase in the level of inhibitor present in culture ofhost cell will increase the number of copies of the marker gene. Sincethe amplified region is associated with the coding sequence of theantibody, production of the antibody will also increase (Crouse et al.,Mol. Cell. Biol. 3:257 (1983)).

[0297] The host cell may be co-transfected with two expression vectorsof the invention, the first vector encoding a heavy chain derivedpolypeptide and the second vector encoding a light chain derivedpolypeptide. The two vectors may contain identical selectable markerswhich enable equal expression of heavy and light chain polypeptides.Alternatively, a single vector may be used which encodes, and is capableof expressing, both heavy and light chain polypeptides. In suchsituations, the light chain is preferably placed before the heavy chainto avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52(1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2 197 (1980)). The codingsequences for the heavy and light chains may comprise cDNA or genomicDNA.

[0298] Once an antibody molecule of the invention has been produced byrecombinant expression, it may be purified by any method known in theart for purification of an immunoglobulin molecule, or more generally,for purification of a protein, for example, by chromatography (e.g., ionexchange, affinity, particularly by affinity for the specific antigenafter Protein A, and sizing column chromatography), centrifugation,differential solubility, or by any other standard technique for thepurification of proteins. Further, the antibodies of the presentinvention may be fused to heterologous polypeptide sequences describedherein or otherwise known in the art to facilitate purification.

[0299] Antibody Characterization

[0300] Antibodies of the present invention (including scFvs and othermolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) may be characterized in a variety of ways. Inparticular, antibodies and related molecules of the invention may beassayed for the ability to immunospecifically bind to BLyS or a fragmentof BLyS (e.g., to the soluble form or the membrane-bound form of BLyS)using techniques described herein or routinely modifying techniquesknown in the art. BLyS or BLyS fragments that may be immunospecificallybound by the compositions of the invention include, but are not limitedto, human BLyS (SEQ ID NOS:3228 and/or 3229) or BLyS expressed on humanmonocytes; murine BLyS (SEQ ID NOS:3230 and/or 3231) or BLyS expressedon murine monocytes; rat BLyS (either the soluble forms as given in SEQID NOS:3232, 3233, 3234 and/or 3235 or in a membrane associated form,e.g., on the surface of rat monocytes); or monkey BLyS (e.g., the monkeyBLyS polypeptides of SEQ ID NOS:3236 and/or 3237, the soluble form ofmonkey BLyS, or BLyS expressed on monkey monocytes) or fragmentsthereof. Preferably compositions of the invention bind human BLyS (SEQID NOS:3228 and/or 3229) or fragments thereof. Assays for the ability ofthe antibodies of the invention to immunospecifically bind BLyS or afragment of BLyS may be performed in solution (e.g., Houghten,Bio/Techniques 13:412-421(1992)), on beads (e.g., Lam, Nature 354:82-84(1991)), on chips (e.g., Fodor, Nature 364:555-556 (1993)), on bacteria(e.g., U.S. Pat. No. 5,223,409), on spores (e.g., Pat. Nos. 5,571,698;5,403,484; and 5,223,409), on plasmids (e.g., Cull et al., Proc. Natl.Acad. Sci. USA 89:1865-1869 (1992)) or on phage (e.g. Scott and Smith,Science 249:386-390 (1990); Devlin, Science 249:404-406 (1990); Cwirlaet al., Proc. Natl. Acad. Sci. USA 87:6378-6382 (1990); and Felici, J.Mol. Biol. 222:301-310 (1991)) (each of these references is incorporatedherein in its entirety by reference). Antibodies that have beenidentified to immunospecifically bind to BLyS or a fragment of BLyS canthen be assayed for their specificity and affinity for BLyS or afragment of BLyS using or routinely modifying techniques describedherein or otherwise known in the art.

[0301] The antibodies of the invention may be assayed for immunospecificbinding to BLyS and cross-reactivity with other antigens by any methodknown in the art. In particular, the ability of an antibody toimmunospecifically bind to the soluble form or membrane-bound form ofBLyS and the specificity of the antibody, fragment, or variant for BLySpolypeptide from a particular species (e.g., murine, monkey or human,preferably human) may be determined using or routinely modifyingtechniques described herein or otherwise known in art.

[0302] Immunoassays which can be used to analyze immunospecific bindingand cross-reactivity include, but are not limited to, competitive andnon-competitive assay systems using techniques such as western blots,radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich”immunoassays, immunoprecipitation assays, precipitin reactions, geldiffusion precipitin reactions, immunodiffusion assays, agglutinationassays, complement-fixation assays, immunoradiometric assays,fluorescent immunoassays, and protein A immunoassays, to name but a few.Such assays are routine and well known in the art (see, e.g., Ausubel etal, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, JohnWiley & Sons, Inc., New York, which is incorporated by reference hereinin its entirety). Exemplary immunoassays are described briefly below(but are not intended by way of limitation).

[0303] Immunoprecipitation protocols generally comprise lysing apopulation of cells in a lysis buffer such as RIPA buffer (1% NP-40 orTriton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 Msodium phosphate at pH 7.2, 1% Trasylol) supplemented with proteinphosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin,sodium vanadate), adding the antibody of interest to the cell lysate,incubating for a period of time (e.g., 1 to 4 hours) at 40 degrees C.,adding protein A and/or protein G sepharose beads to the cell lysate,incubating for about an hour or more at 40 degrees C., washing the beadsin lysis buffer and resuspending the beads in SDS/sample buffer. Theability of the antibody of interest to immunoprecipitate a particularantigen can be assessed by, e.g., western blot analysis. One of skill inthe art would be knowledgeable as to the parameters that can be modifiedto increase the binding of the antibody to an antigen and decrease thebackground (e.g., pre-clearing the cell lysate with sepharose beads).For further discussion regarding immunoprecipitation protocols see,e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology,Vol. 1, John Wiley & Sons, Inc., New York at 10.16.1.

[0304] Western blot analysis generally comprises preparing proteinsamples, electrophoresis of the protein samples in a polyacrylamide gel(e.g., 8%-20% SDS-PAGE depending on the molecular weight of theantigen), transferring the protein sample from the polyacrylamide gel toa membrane such as nitrocellulose, PVDF or nylon, blocking the membranein blocking solution (e.g., PBS with 3% BSA or non-fat milk), washingthe membrane in washing buffer (e.g., PBS-Tween 20), blocking themembrane with primary antibody (the antibody of interest) diluted inblocking buffer, washing the membrane in washing buffer, blocking themembrane with a secondary antibody (which recognizes the primaryantibody, e.g., an anti-human antibody) conjugated to an enzymaticsubstrate (e.g., horseradish peroxidase or alkaline phosphatase) orradioactive molecule (e.g. ³²P or ¹²⁵I) diluted in blocking buffer,washing the membrane in wash buffer, and detecting the presence of theantigen. One of skill in the art would be knowledgeable as to theparameters that can be modified to increase the signal detected and toreduce the background noise. For further discussion regarding westernblot protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols inMolecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.8.1.

[0305] ELISAs comprise preparing antigen, coating the well of a 96-wellmicrotiter plate with the antigen, washing away antigen that did notbind the wells, adding the antibody of interest conjugated to adetectable compound such as an enzymatic substrate (e.g., horseradishperoxidase or alkaline phosphatase) to the wells and incubating for aperiod of time, washing away unbound antibodies or non-specificallybound antibodies, and detecting the presence of the antibodiesspecifically bound to the antigen coating the well. In ELISAs theantibody of interest does not have to be conjugated to a detectablecompound; instead, a second antibody (which recognizes the antibody ofinterest) conjugated to a detectable compound may be added to the well.Further, instead of coating the well with the antigen, the antibody maybe coated to the well. In this case, the detectable molecule could bethe antigen conjugated to a detectable compound such as an enzymaticsubstrate (e.g., horseradish peroxidase or alkaline phosphatase). One ofskill in the art would be knowledgeable as to the parameters that can bemodified to increase the signal detected as well as other variations ofELISAs known in the art. For further discussion regarding ELISAs see,e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology,Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1.

[0306] The binding affinity of an antibody (including an scFv or othermolecule comprising, or alternatively consisting of, antibody fragmentsor variants thereof) to an antigen and the off-rate of anantibody-antigen interaction can be determined by competitive bindingassays. One example of a competitive binding assay is a radioimmunoassaycomprising the incubation of labeled antigen (e.g., ³H or ¹²⁵I) with theantibody of interest in the presence of increasing amounts of unlabeledantigen, and the detection of the antibody bound to the labeled antigen.The affinity of the antibody of the present invention for BLyS and thebinding off-rates can be determined from the data by Scatchard plotanalysis. Competition with a second antibody can also be determinedusing radioimmunoassays. In this case, BLyS is incubated with anantibody of the present invention conjugated to a labeled compound(e.g., ³H or ¹²⁵I) in the presence of increasing amounts of an unlabeledsecond anti-BLyS antibody.

[0307] In a preferred embodiment, BIAcore kinetic analysis is used todetermine the binding on and off rates of antibodies (including an scFvor other molecule comprising, or alternatively consisting of, antibodyfragments or variants thereof) to BLyS, or fragments of BLyS. BIAcorekinetic analysis comprises analyzing the binding and dissociation ofBLyS from chips with immobilized antibodies on their surface asdescribed in detail in Examples 6, 12, 17 and 18, infra.

[0308] The antibodies of the invention (including scFvs and othermolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) can also be assayed for their ability to inhibit,increase, or not significantly alter, the binding of BLyS to a BLySreceptor (e.g., TACI and BCMA) using techniques known to those of skillin the art. For example, cells expressing a receptor for BLyS (e.g.,IM9, REH, ARH-77 cells, Namalwa, and RPMI-8226 B cell tumor lines aswells as peripheral CD20+ B cells) can be contacted with BLyS in thepresence or absence of an antibody, and the ability of the antibody toinhibit, increase, or not significantly alter, BLyS binding to the cellscan be measured. BLyS binding to cells can be measured by, for example,flow cytometry or a scintillation assay. BLyS or the antibody can belabeled with a detectable compound such as a radioactive label (e.g.,³²P, ³⁵S, and ¹²⁵I) or a fluorescent label (e.g., fluoresceinisothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin,o-phthaldehyde and fluorescamine) to enable detection of an interactionbetween BLyS and a BLyS receptor and/or BLyS and an antibody of theinvention. Alternatively, the ability of antibodies of the invention toinhibit, increase, or not significantly alter, BLyS binding to a BLySreceptor can be determined in cell-free assays. For example, native orrecombinant BLyS (e.g., that having the amino acid sequence of aminoacids 134-285 of SEQ ID NO:3228) or a fragment thereof can be contactedwith an antibody and the ability of the antibody to inhibit, increase,or not significantly alter, BLyS from binding to a BLyS receptor can bedetermined. Preferably, the antibody is immobilized on a solid supportand BLyS or a BLyS fragment is labeled with a detectable compound.Alternatively, BLyS or a BLyS fragment is immobilized on a solid supportand the antibody is labeled with a detectable compound. BLyS may bepartially or completely purified (e.g., partially or completely free ofother polypeptides) or part of a cell lysate. Further, the BLySpolypeptide may be a fusion protein comprising BLyS or a biologicallyactive portion thereof and a domain such as an immunoglobulin Fc orglutathionine-S-transferase. For example, amino acid residues 1-154 ofTACI (GenBank accession number AAC51790), or 1-48 of BCMA (GenBankaccession number NP_(—)001183) may be fused to the Fc region of an IgGmolecule and used in a cell free assay to determine the ability ofantibodies of the invention to inhibit, increase, or not significantlyalter, BLyS binding to a BLyS receptor. Alternatively, BLyS can bebiotinylated using techniques well known to those of skill in the art(e.g., biotinylation kit, Pierce Chemicals; Rockford, Ill.).

[0309] The antibodies of the invention (including scFvs or othermolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof), can also be assayed for their ability to inhibit,stimulate, or not significantly alter, BLyS-induced B-cell proliferationusing techniques known to those of skill in the art. For example, B-cellproliferation can be assayed by ³H-thymidine incorporation assays andtrypan blue cell counts (see, e.g., Moore et al., Science 285: 260-263(1999)). Further, the antibodies of the invention, or fragments orvariants thereof, can be assayed for their ability to block, stimulate,or not significantly alter, BLyS-induced activation of cellularsignaling molecules and transcription factors such as calcium-modulatorand cyclophilin ligand (“CAML”), calcineurin, nuclear factor ofactivated T cells transcription factor (“NF-AT”), nuclear factor-kappa B(“NF-kappa B”), and AP-1 using techniques known to those of skill in theart (see, e.g., von Bulow and Bram, Science 278:138-141(1997)). Forexample, NF-AT activity can be determined by electromobility gel shiftassays, by detecting the expression of a protein known to be regulatedby NF-AT (e.g., IL-2 expression), by detecting the induction of areporter gene (e.g., an NF-AT regulatory element operably linked to anucleic acid encoding a detectable marker such as luciferase,beta-galactosidase or chloramphenicol acetyltransferase (CAT)), or bydetecting a cellular response (e.g., cellular differentiation, or cellproliferation).

[0310] The antibodies of the invention, or fragments or variants thereofcan also be assayed for their ability to neutralize, enhance, or notsignificantly alter, BLyS activity. For example, antibodies or fragmentsor variants thereof, may be routinely tested for their ability toinhibit BLyS from binding to cells expressing the receptor for BLyS (seeExample 3, infra).

[0311] Selection and Screening for Antibodies that ImmunospecificallyBind to Soluble BLyS

[0312] Antibodies of the invention (including scFvs and other moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) may be screened in a variety of assays to identifythose antibodies that immunospecifically bind to the soluble form ofBLyS. In one particular assay, antibodies that bind to the biotinylatedsoluble form of BLyS in solution are captured on streptavidin coatedmagnetic beads. This assay may be relatively applied to identifyantibodies of the invention that neutralize and/or bind to BLyS.Additionally, antibodies may be assayed in neutralization assaysdescribed herein or otherwise known in the art (see Example 3, infra).For example, antibodies may be tested for their ability to inhibitsoluble BLyS (e.g., biotinylated BLyS) from binding to IM9 cells. Inthis assay, labeled soluble BLyS (e.g., biotinylated BLyS) is incubatedwith candidate anti-BLyS antibodies to allow for the formation ofBLyS-anti-BLyS antibody complexes. Following incubation, an aliquot ofthe BLyS-anti-BLyS antibody sample is added to IM9 cells. The binding ofsoluble BLyS may be determined using techniques known in the art. Forexample, the binding of biotinylated BLyS to IM9 cells may be detectedusing a fluorimeter following the addition of streptavidin-delfia.Biotinylated BLyS, if it is not bound by antibodies that neutralizeBLyS, binds to the cells is detected. Thus, an antibody that decreasesthe amount of bio-BLyS that binds to IM-9 cells (relative to a controlsample in which the BLyS had been preincubated with an irrelevantantibody or no antibody at all) is identified as one that binds to andneutralizes the soluble form of BLyS. In another assay, antibodies arescreened using ELISAs for those antibodies that bind to biotinylatedsoluble BLyS, but do not bind membrane-bound BLyS, such as, for example,BLyS on membranes from U937 cells (see Examples 2 and 9, infra). Inthese assays, soluble BLyS (e.g., biotinylated BLyS) and membrane-boundBLyS (e.g., on U937 membranes) are incubated in separate samples withthe same antibodies and those antibodies that bind to the soluble BLyS(biotinylated BLyS), but not membrane-bound BLyS (e.g., on U937membranes) are captured and identified.

[0313] Antibodies of the invention (including scFvs and other moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) may be tested to identify those antibodies that do notcross-react with APRIL, endokine-alpha, VEGI, TRAIL, TNF-alpha,TNF-beta, Fas-L, LIGHT, and PBS (see Example 4, infra). Antibodies mayalso be tested for their affinity for BLyS using, for example, BIAcoreanalysis (see Examples 6, 12, 17 and 18 infra). Antibodies may also betested for their ability to stimulate, inhibit, or not alter,BLyS-induced immunoglobulin production and/or B-cell proliferation usingtechniques known to those of skill in the art. For example, humanB-cells, BLyS and antibodies may be incubated together in 96 well platesand ³H-thymidine incorporation may be measured using a scintillationcounter.

[0314] Selection and Screening for Antibodies that ImmunospecificallyBind to Membrane-bound BLyS

[0315] Antibodies of the invention (including scFvs and other moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) may be screened in a variety of assays to identifythose antibodies that immunospecifically bind to the membrane-bound formof BLyS. In one particular assay, antibodies that bind to BLyS on U937membranes or immobilized histidine-tagged BLyS are captured. Other celllines that express BLyS that might be useful for testing antibodybinding to membrane-bound form of BLyS include, K-562, HL-60 and THP-1cells. In another assay, antibodies are screened using ELISAs for thoseantibodies (or antibody fragments or variants) that bind to BLyS on U937membranes or to histidine-tagged BLyS. In this assay, antibodies areadded to 96 well plates coated with U937 membranes or histidine-taggedBLyS and those antibodies or antibody fragments or variants that bind tothe U937 membranes or histidine-tagged BLyS are captured. In anotherassay, antibodies are screened using ELISAs for those antibodies (orantibody fragments or variants thereof) that do not bind to biotinylatedBLyS (soluble BLyS) but bind to membrane-bound BLyS, such as, forexample, that on membranes from U937 cells (see Example 2, infra). Inthese assays, soluble BLyS (e.g., biotinylated BLyS) and membrane-boundBLyS (e.g., on U937 membranes) are incubated in separate samples withthe same antibodies (or antibody fragments or variants) and thoseantibodies (or antibody fragments or variants) that do not bind to thesoluble BLyS (biotinylated BLyS), but bind the membrane-bound BLyS(e.g., on U937 membranes) are captured and identified. In other assays,antibodies are screened using ELISAs to determine which of theantibodies (or antibody fragments or variants) that bind tohistidine-tagged BLyS or membranes from U937 cells do not cross-reactwith APRIL, endokine-alpha, VEGI, TRAIL, TNF-alpha, TNF-beta, Fas-L,LIGHT, and PBS (See Example 4, infra). ELISAs can also be used todetermine which of the antibodies (or antibody fragments or variants)that bind to histidine-tagged BLyS or membranes from U937 cells bind toBLyS in the presence of TNF-alpha (see Example 4, infra). Antibodies orfragments or variants thereof that immunospecifically bind to themembrane-bound form of BLyS may also be tested for their affinity forhistidine-tagged BLyS using high-throughput BIAcore analysis (seeExample 14, infra).

[0316] Additionally, antibodies of the invention may be screened againstcells engineered to express an “uncleavable” form of BLyS in order todetermine their specificity for the membrane-bound form of BLyS.Mutations in BLyS which may achieve this result include, but are notlimited to, the mutation or deletion of amino acid residues Lys-132and/or Arg-133 of the BLyS sequence shown in SEQ ID NO:3228. A typicalmutagenesis might include mutation of one or both of residues Lys-132 orArg-133 to alanine residues. Cells expressing such an “uncleavable” formof BLyS provide a profound reagent to use in assaying the ability ofantibodies to bind the membrane-bound form of BLyS.

[0317] Selection and Screening for Antibodies that ImmunospecificallyBind to Soluble and Membrane-bound BLyS

[0318] Antibodies of the invention (including scFvs and other moleculescomprising, or alternately consisting of, antibody fragments orvariants) may be screened in a variety of assays to identify thoseantibodies or antibody fragments or variants that immunospecificallybind to the soluble form and membrane-bound form of BLyS. In oneparticular assay, antibodies that bind to immobilized BLyS are captured.In another assay, antibodies are screened using ELISAs for thoseantibodies (or antibody fragments or variants) that inhibit the bindingof soluble BLyS (e.g. soluble bio-BLyS) to IM-9 cells as describedsupra. In other assays, antibodies are screened using ELISAs for thoseantibodies that bind to membranes from U937 cells. Additionally, furtherELISA assays may be performed using techniques known in the art todetermine which antibodies do not cross-react with APRIL,endokine-alpha, VEGI, TRAIL, TNF-alpha, TNF-beta, Fas-L, LIGHT, and PBS,or those antibodies that bind to BLyS in the presence of TNF-alpha (seeExample 4 infra). Antibodies may be assayed in neutralization assaysusing techniques described herein or otherwise known in the art.Antibodies that immunospecifically bind to the soluble andmembrane-bound forms of BLyS may also be tested for their affinity forBLyS using high-throughput BIAcore analysis.

[0319] Antibody Conjugates

[0320] The present invention encompasses antibodies (including scFvs andother molecules comprising, or alternatively consisting of, antibodyfragments or variants thereof), recombinantly fused or chemicallyconjugated (including both covalent and non-covalent conjugations) to aheterologous polypeptide (or portion thereof, preferably at least 10, atleast 20, at least 30, at least 40, at least 50, at least 60, at least70, at least 80, at least 90 or at least 100 amino acids of thepolypeptide) to generate fusion proteins. The fusion does notnecessarily need to be direct, but may occur through linker sequences.For example, antibodies of the invention may be used to targetheterologous polypeptides to particular cell types (e.g., cells ofmonocytic lineage and B-cells), either in vitro or in vivo, by fusing orconjugating the heterologous polypeptides to antibodies of the inventionthat are specific for particular cell surface antigens (e.g.,membrane-bound BLyS on cells of monocytic lineage) or which bindantigens that bind particular cell surface receptors (e.g., TACI and/orBCMA located on B cells). Antibodies fused or conjugated to heterologouspolypeptides may also be used in in vitro immunoassays and purificationmethods using methods known in the art. See e.g., Harbor et al., supra,and PCT publication WO 93/2 1232; EP 439,095; Naramura et al., Immunol.Lett. 39:91-99 (1994); U.S. Pat. No. 5,474,981; Gillies et al, PNAS89:1428-1432 (1992); Fell et al., J. Immunol. 146:2446-2452 (1991),which are incorporated by reference in their entireties.

[0321] In one embodiment, a fusion protein comprises a polypeptidehaving an amino acid sequence of any one of the VH domains referred toin Table 1, and a heterologous polypeptide. In another embodiment, afusion protein comprises a polypeptide having the amino acid sequence ofany one of the VH CDR1s referred to in Table 1, and a heterologouspolypeptide. In another embodiment, a fusion protein comprises apolypeptide having the amino acid sequence of any one of the VH CDR2sreferred to in Table 1, and a heterologous polypeptide. In a preferredembodiment, a fusion protein comprises a polypeptide having the aminoacid sequence of any one of the VH CDR3s referred to in Table 1 (i.e.,SEQ ID NOS:2129-3227), and a heterologous polypeptide.

[0322] In another embodiment, a fusion protein comprises a polypeptidehaving the amino acid sequence of any one of the VL domains referred toin Table 1, and a heterologous polypeptide. In another embodiment, afusion protein comprises a polypeptide having the amino acid sequence ofany one of the VL CDR1s referred to in Table 1, and a heterologouspolypeptide. In yet another embodiment, a fusion protein comprises apolypeptide having the amino acid sequence of any one of the VL CDR2sreferred to in Table 1, and a heterologous polypeptide. In a preferredembodiment, a fusion protein comprises a polypeptide having the aminoacid sequence of any one of the VL CDR3s referred to in Table 1, and aheterologous polypeptide.

[0323] In another embodiment, a fusion protein comprises a polypeptidehaving the amino acid sequence of any one of the VH domains referred toin Table 1, and one or more VL domains referred to in Table 1, and aheterologous polypeptide. In another embodiment, a fusion protein of thepresent invention comprises a polypeptide having the amino acid sequenceof any one of the VH CDRs referred to in Table 1, and any one of the VLCDRs referred to in Table 1, and a heterologous polypeptide.

[0324] The present invention further includes compositions comprising,or alternatively consisting of, heterologous polypeptides fused orconjugated to antibody fragments. For example, the heterologouspolypeptides may be fused or conjugated to a Fab fragment, Fd fragment,Fv fragment, F(ab)₂ fragment, or a portion thereof. Methods for fusingor conjugating polypeptides to antibody portions are known in the art.See, e.g., U.S. Pat. Nos. 5,336,603; 5,622,929; 5,359,046; 5,349,053;5,447,851; 5,112,946; EP 307,434; EP 367,166; PCT publications WO96/04388; WO 91/06570; Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535-10539 (1991); Zheng et al, J. Immunol. 154:5590-5600 (1995); andVil et al., Proc. Natl. Acad. Sci. USA 89:11337-11341 (1992) (saidreferences incorporated by reference in their entireties).

[0325] Additional fusion proteins of the invention may be generatedthrough the techniques of gene-shuffling, motif-shuffling,exon-shuffling, and/or codon-shuffling (collectively referred to as “DNAshuffling”). DNA shuffling may be employed to modulate the activities ofantibodies (including scFvs and other molecules comprising, oralternatively consisting of, antibody fragments or variants thereof),such methods can be used to generate antibodies with altered activity(e.g., antibodies with higher affinities and lower dissociation rates).See, generally, U.S. Pat. Nos. 5,605,793; 5,811,238; 5,830,721;5,834,252; and 5,837,458, and Patten et al., Curr. Opinion Biotechnol.8:724-33 (1997); Harayama, Trends Biotechnol. 16(2):76-82 (1998);Hansson, et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo andBlasco, Biotechniques 24(2):308-13 (1998) (each of these patents andpublications are hereby incorporated by reference in its entirety). Inone embodiment, polynucleotides encoding antibodies of the invention maybe altered by being subjected to random mutagenesis by error-prone PCR,random nucleotide insertion or other methods prior to recombination. Inanother embodiment, one or more portions of a polynucleotide encoding anantibody which portions immunospecifically bind to BLyS may berecombined with one or more components, motifs, sections, parts,domains, fragments, etc. of one or more heterologous molecules.

[0326] Moreover, the antibodies of the present invention (includingscFvs and other molecules comprising, or alternatively consisting of,antibody fragments or variants thereof), can be fused to markersequences, such as a polypeptides to facilitate purification. Inpreferred embodiments, the marker amino acid sequence is ahexa-histidine polypeptide, such as the tag provided in a pQE vector(QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), amongothers, many of which are commercially available. As described in Gentzet al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance,hexa-histidine provides for convenient purification of the fusionprotein. Other peptide tags useful for purification include, but are notlimited to, the hemagglutinin “HA” tag, which corresponds to an epitopederived from the influenza hemagglutinin protein (Wilson et al., Cell37:767 (1984)) and the “flag” tag (DYKDDDDK, (SEQ ID No: 3238)Stratagene, La Jolla, Calif.).

[0327] The present invention further encompasses antibodies (includingscFvs and other molecules comprising, or alternatively consisting of,antibody fragments or variants thereof), conjugated to a diagnostic ortherapeutic agent. The antibodies can be used diagnostically to, forexample, monitor or prognose the development or progression of a tumoras part of a clinical testing procedure to, e.g., determine the efficacyof a given treatment regimen. Detection can be facilitated by couplingthe antibody to a detectable substance. Examples of detectablesubstances include, but are not limited to, various enzymes, prostheticgroups, fluorescent materials, luminescent materials, bioluminescentmaterials, radioactive materials, positron emitting metals using variouspositron emission tomographies, and nonradioactive paramagnetic metalions. The detectable substance may be coupled or conjugated eitherdirectly to the antibody or indirectly, through an intermediate (suchas, for example, a linker known in the art) using techniques known inthe art. See, for example, U.S. Pat. No. 4,741,900 for metal ions whichcan be conjugated to antibodies for use as diagnostics according to thepresent invention. Examples of suitable enzymes include, but are notlimited to, horseradish peroxidase, alkaline phosphatase,beta-galactosidase, or acetylcholinesterase; examples of suitableprosthetic group complexes include, but are not limited to,streptavidinlbiotin and avidin/biotin; examples of suitable fluorescentmaterials include, but are not limited to, umbelliferone, fluorescein,fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride or phycoerythrin; an example of aluminescent material includes, but is not limited to, luminol; examplesof bioluminescent materials include, but are not limited to, luciferase,luciferin, and aequorin; and examples of suitable radioactive materialinclude, but are not limited to, iodine (¹³¹I, ¹²⁵I, ¹²³I, ¹²¹I), carbon(¹⁴C), sulfur (³⁵S), tritium (³H), indium (^(115m)In, ^(113m)In, ¹¹²In,¹¹¹In), and technetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium(⁶⁸Ga, ⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe),fluorine (¹⁸F), ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y,⁴⁷Sc, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru, ⁶⁸Ge, ⁵⁷Co, ⁶⁵Zn, ⁸⁵Sr, ³²P,¹⁵³Gd, ¹⁶⁹Yb, ⁵¹Cr, ⁵⁴Mn, ⁷⁵Se, ¹¹³Sn, and ¹¹⁷Tin.

[0328] Further, an antibody of the invention (including an scFv or othermolecule comprising, or alternatively consisting of, antibody fragmentsor variants thereof), may be conjugated to a therapeutic moiety such asa cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agentor a radioactive metal ion, e.g., alpha-emitters such as, for example,²¹³Bi. In specific embodiments, antibodies of the invention are attachedto macrocyclic chelators useful for conjugating radiometal ions,including but not limited to, ¹¹¹In, ¹⁷⁷Lu, ⁹⁰Y, ¹⁶⁶Ho, and ¹⁵³Sm, topolypeptides. In preferred embodiments, the radiometal ion associatedwith the macrocyclic chelators attached to antibodies of the inventionis ¹¹¹In. In preferred embodiments, the radiometal ion associated withthe macrocyclic chelators attached to antibodies of the invention is⁹⁰Y. In specific embodiments, the macrocyclic chelator is1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA). Inother specific embodiments, the DOTA is attached to the antibody of theinvention via a linker molecule. Examples of linker molecules useful forconjugating DOTA to a polypeptide are commonly known in the art—see, forexample, DeNardo et al., Clin Cancer Res. 4(10):2483-90, 1998; Petersonet al., Bioconjug. Chem. 10(4):553-7, 1999; and Zimmerman et al, Nucl.Med. Biol. 26(8):943-50, 1999 which are hereby incorporated by referencein their entirety.

[0329] A cytotoxin or cytotoxic agent includes any agent that isdetrimental to cells and includes such molecules as small moleculetoxins and enzymatically active toxins of bacterial, fungal, plant, oranimal origin, or fragments thereof Examples include, but are notlimited to, paclitaxol, cytochalasin B, gramicidin D, ethidium bromide,emetine, mitomycin, etoposide (VP-16), tenoposide, vincristine,vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracindione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone,glucocorticoids, procaine, tetracaine, lidocaine, propranolol, thymidinekinase, endonuclease, RNAse, and puromycin and frragments, variants orhomologs thereof. Therapeutic agents include, but are not limited to,antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine,cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g.,mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cisdichlorodiamine platinum (II) (DDP)cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) anddoxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin),bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents(e.g., vincristine and vinblastine), improsulfan, piposulfan, benzodopa,carboquone, meturedopa, uredopa, altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramidetrimethylolomelamine, chlornaphazine, cholophosphamide, estramustine,ifosfamide, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard, chlorozotocin, fotemustine, nimustine, ranimustine,aclacinomysins, azaserine, cactinomycin, calicheamicin, carabicin,carminomycin, carzinophilin, chromomycins, detorubicin,6-diazo-5-oxo-L-norleucine, epirubicin, esorubicin, idarubicin,marcellomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin,potfiromycin, quelamycin, rodorubicin, streptonigrin, tubercidin,ubenimex, zinostatin, zorubicin, denopterin, pteropterin, trimetrexate,fludarabine, thiamiprine, ancitabine, azacitidine, 6-azauridine,carmofur, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU,calusterone, dromostanolone propionate, epitiostanol, mepitiostane,testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid,aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine,bestrabucil, bisantrene, edatraxate, defofamine, dernecolcine,diaziquone, elfornithine, elliptiniurn acetate, etoglucid, galliumnitrate, hydroxyurea, lentinan, lonidamine, mitoguazone, mopidamol,nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid,2-ethylhydrazide, procarbazine, PSKO, razoxane, sizofiran,spirogermanium, tenuazonic acid, triaziquone,2,2′,2″-trichlorotriethylamine, urethan, vindesine, dacarbazine,mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine,arabinoside (“Ara-C”), taxoids, e.g. paclitaxel (TAXOL″, Bristol-MyersSquibb Oncology, Princeton, N.J.) doxetaxel (TAXOTERE″, Rh6ne-PoulencRorer, Antony, France), gemcitabine, ifosfamide, vinorelbine, navelbine,novantrone, teniposide, aminopterin, xeloda, ibandronate, CPT-I1,topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO),retinoic acid, esperamicins, capecitabine, and pharmaceuticallyacceptable salts, acids or derivatives of any of the above. Alsoincluded in this definition are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, raloxifene, aromatase inhibiting4(5)-imidazoles, 4 hydroxytamoxifen, trioxifene, keoxifene, LY 117018,onapristone, toremifene (Fareston), and anti-androgens such asflutamide, nilutamide, bicalutamide, leuprolide, and goserelin, andpharmaceutically acceptable salts, acids or derivatives of any of theabove.

[0330] Techniques known in the art may be applied to label antibodies ofthe invention. Such techniques include, but are not limited to, the useof bifunctional conjugating agents (see e.g., U.S. Pat. Nos. 5,756,065;5,714,631; 5,696,239; 5,652,361; 5,505,931; 5,489,425; 5,435,990;5,428,139; 5,342,604; 5,274,119; 4,994,560; and 5,808,003; the contentsof each of which are hereby incorporated by reference in its entirety)and direct coupling reactions (e.g., Bolton-Hunter and Chloramine-Treaction).

[0331] The antibodies of the invention which are conjugates can be usedfor modifying a given biological response, the therapeutic agent or drugmoiety is not to be construed as limited to classical chemicaltherapeutic agents. For example, the drug moiety may be a protein orpolypeptide possessing a desired biological activity. Such proteins mayinclude, but are not limited to, for example, a toxin such as abrin,ricin A, alpha toxin, pseudomonas exotoxin, or diphtheria toxin,saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin andcholera toxin; a protein such as tumor necrosis factor,alpha-interferon, beta-interferon, nerve growth factor, platelet derivedgrowth factor, tissue plasminogen activator, an apoptotic agent, e.g.,TNF-alpha, TNF-beta, AIM I (see, International Publication No. WO97/33899), AIM II (see, International Publication No. WO 97/34911), FasLigand (Takahashi et al., Int. Immunol., 6:1567-1574 (1994)), VEGI (see,International Publication No. WO 99/23105), a thrombotic agent or ananti-angiogenic agent, e.g., angiostatin or endostatin; or, biologicalresponse modifiers such as, for example, lymphokines, interleukin-1(IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocytemacrophage colony stimulating factor (GM-CSF), granulocyte colonystimulating factor (G-CSF), or other growth factors.

[0332] Antibodies of the invention (including scFvs and other moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof), may also be attached to solid supports, which areparticularly useful for immunoassays or purification of the targetantigen. Such solid supports include, but are not limited to, glass,cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride orpolypropylene.

[0333] Techniques for conjugating a therapeutic moiety to antibodies arewell known, see, e.g., Arnon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al, “ThePreparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol. Rev. 62:119-58 (1982).

[0334] Alternatively, an antibody of the invention can be conjugated toa second antibody to form an antibody heteroconjugate as described bySegal in U.S. Pat. No. 4,676,980, which is incorporated herein byreference in its entirety.

[0335] An antibody of the invention (including an scFv or and othermolecule comprising, or alternatively consisting of, an antibodyfragment or variant thereof), with or without a therapeutic moietyconjugated to it, administered alone or in combination with cytotoxicfactor(s) and/or cytokine(s) can be used as a therapeutic.

[0336] Use of Antibodies for Epitope Mapping

[0337] The present invention provides antibodies (including scFvs andother molecules comprising, or alternatively consisting of, antibodyfragments or variants thereof), that can be used to identify epitopes ofBLyS. In particular, the antibodies of the present invention can be usedto identify epitopes of human BLyS (SEQ ID NOS:3228 and/or 3229) or BLySexpressed on human monocytes; murine BLyS (SEQ ID NOS:3230 and/or 3231)or BLyS expressed on murine monocytes; rat BLyS (either the solubleforms as given in SEQ ID NOS:3232, 3233, 3234 and/or 3235 or in amembrane associated form, e.g., on the surface of rat monocytes); ormonkey BLyS (e.g., the monkey BLyS polypeptides of SEQ ID NOS:3236and/or 3237, the soluble form of monkey BLyS, or BLyS expressed onmonkey monocytes) using techniques described herein or otherwise knownin the art. Fragments which function as epitopes may be produced by anyconventional means. (See, e.g., Houghten, Proc. Natl. Acad. Sci. USA82:5131-5135 (1985), firther described in U.S. Pat. No. 4,631,211.)

[0338] Diagnostic Uses of Antibodies

[0339] Labeled antibodies of the invention (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) which specifically bind to BLyS can be used fordiagnostic purposes to detect, diagnose, prognose, or monitor diseasesand/or disorders associated with the aberrant expression and/or activityof BLyS or BLyS receptor. The invention provides for the detection ofaberrant expression of BLyS comprising: (a) assaying the expression ofBLyS in a biological sample from an individual using one or moreantibodies of the invention that immunospecifically binds to BLyS; and(b) comparing the level of BLyS with a standard level of BLyS, e.g., innormal biological samples, whereby an increase or decrease in theassayed level of BLyS compared to the standard level of BLyS isindicative of aberrant expression.

[0340] By “biological sample” is intended any fluids and/or cellsobtained from an individual, body fluid, body tissue, body cell, cellline, tissue culture, or other source which may contain BLyS protein ormRNA. Body fluids include, but are not limited to, sera, plasma, urine,synovial fluid, spinal fluid, saliva, and mucous. Tissues samples may betaken from virtually any tissue in the body. Tissue samples may also beobtained from autopsy material. Methods for obtaining tissue biopsiesand body fluids from mammals are well known in the art. Where thebiological sample is to include mRNA, a tissue biopsy is the preferredsource.

[0341] The invention also provides for the detection of aberrantexpression of BLyS receptor comprising (a) assaying the expression ofBLyS receptor in a biological sample from an individual using one ormore antibodies or fragments or variants thereof that immunospecificallybinds only to soluble BLyS, but does not inhibit BLyS/BLyS receptorbinding. Such an antibody, by way of an example that is not to beconstrued as limiting, would be one that is able to capture abiotinylated BLyS from solution (see Example 8), but that would notprevent BLyS from binding to IM-9 cells (see Example 3). and (b)comparing the level of BLyS receptor with a standard level of BLySreceptor, e.g., in normal tissue or cell samples, whereby an increase ordecrease in the assayed level of BLyS receptor compared to the standardlevel of BLyS receptor is indicative of aberrant expression.

[0342] Antibodies of the invention (including molecules comprising, oralternatively consisting of, antibody fragments or variants thereof)which specifically bind to BLyS can be used for diagnostic purposes todetect, diagnose, prognose, or monitor autoimmune disorders and/orimmunodeficiencies, and/or diseases or conditions associated therewith.The invention provides for the detection of aberrant expression of BLyScomprising: (a) assaying the expression of BLyS in a biological samplefrom an individual using one or more antibodies of the invention thatimmunospecifically binds to BLyS; and (b) comparing the level of BLySwith a standard level of BLyS, e.g., in normal biological samples,whereby an increase or decrease in the assayed level of BLyS compared tothe standard level of BLyS is indicative of an autoimmune disorder ordisease and/or an immunodeficiency. In specific embodiments, an increasein the assayed level of BLyS is indicative of an autoimmune disorder ordisease. In other specific embodiments, a decrease in the assayed levelof BLyS is indicative of an immunodeficiency.

[0343] Antibodies of the invention (including molecules comprising, oralternatively consisting of, antibody fragments or variants thereof)which specifically bind to BLyS but, do not inhibit BLyS/BLyS receptorbinding can be used for diagnostic purposes to detect, diagnose,prognose, or monitor autoimmune disorders and/or immunodeficiencies,and/or diseases or conditions associated therewith. The inventionprovides for the detection of aberrant expression of BLyS receptorcomprising: (a) assaying the expression of BLyS receptor in a biologicalsample from an individual using one or more antibodies of the inventionthat immunospecifically binds to BLyS; and (b) comparing the level ofBLyS receptor with a standard level of BLyS receptor, e.g., in normalbiological samples, whereby an increase or decrease in the assayed levelof BLyS receptor compared to the standard level of BLyS receptor isindicative of an autoimmune disorder or disease and/or animmunodeficiency. In specific embodiments, an increase in the assayedlevel of BLyS receptor is indicative of an autoimmune disorder ordisease. In other specific embodiments, a decrease in the assayed levelof BLyS receptor is indicative of an immunodeficiency.

[0344] Autoimmune disorders, diseases, or conditions that may bedetected, diagnosed, prognosed, or monitored using the antibodies of theinvention include, but are not limited to, autoimmune hemolytic anemia,autoimmune neonatal thrombocytopenia, idiopathic thrombocytopeniapurpura, autoimmune neutropenia, autoimmunocytopenia, hemolytic anemia,antiphospholipid syndrome, dermatitis, gluten-sensitive enteropathy,allergic encephalomyelitis, myocarditis, relapsing polychondritis,rheumatic heart disease, glomerulonephritis (e.g., IgA nephropathy),Multiple Sclerosis, Neuritis, Uveitis Ophthalmia, Polyendocrinopathies,Purpura (e.g., Henloch-Scoenlein purpura), Reiter's Disease, Stiff-ManSyndrome, Autoimmune Pulmonary Inflammation, myocarditis, IgAglomerulonephritis, dense deposit disease, rheumatic heart disease,Guillain-Barre Syndrome, diabetes mellitus (e.g. Type I diabetesmellitus or insulin dependent diabetes mellitis), juvenile onsetdiabetes, and autoimmune inflammatory eye, autoimmune thyroiditis,hypothyroidism (i.e., Hashimoto's thyroiditis, systemic lupuserhythematosus, discoid lupus, Goodpasture's syndrome, Pemphigus,Receptor autoimmunities such as, for example, (a) Graves' Disease, (b)Myasthenia Gravis, and (c) insulin resistance, autoimmune hemolyticanemia, autoimmune thrombocytopenic purpura, rheumatoid arthritis,schleroderma with anti-collagen antibodies, mixed connective tissuedisease, polymyositis/dermatomyositis, pernicious anemia (Addison'sdisease), idiopathic Addison's disease, infertility, glomerulonephritissuch as primary glomerulonephritis and IgA nephropathy, bullouspemphigoid, Sjögren's syndrome, diabetes millitus, and adrenergic drugresistance (including adrenergic drug resistance with asthma or cysticfibrosis), chronic active hepatitis, primary biliary cirrhosis, otherendocrine gland failure, vitiligo, vasculitis, post-MI, cardiotomysyndrome, urticaria, atopic dermatitis, asthma, inflammatory myopathies,and other inflammatory, granulomatous, degenerative, and atrophicdisorders and other disorders such as inflammatory skin diseasesincluding psoriasis and sclerosis, responses associated withinflammatory bowel disease (such as Crohn's disease and ulcerativecolitis), respiratory distress syndrome (including adult respiratorydistress syndrome, ARDS), meningitis, encephalitis, colitis, allergicconditions such as eczema and other conditions involving infiltration ofT cells and chronic inflammatory responses, atherosclerosis, leukocyteadhesion deficiency, Reynaud's syndrome, and immune responses associatedwith acute and delayed hypersensitivity mediated by cytokines andT-lymphocytes typically found in tuberculosis, sarcoidosis,granulomatosis and diseases involving leukocyte diapedesis, centralnervous system (CNS) inflammatory disorder, multiple organ injurysyndrome, antigen-antibody complex mediated diseases, anti-glomerularbasement membrane disease, Lambert-Eaton myasthenic syndrome, Beheetdisease, giant cell arteritis, immune complex nephritis, IgAnephropathy, IgM polyneuropathies or autoimmune thrombocytopenia etc.

[0345] In specific embodiments, the present invention encompassesmethods and compositions for detecting, diagnosing and/or prognosingdiseases or disorders associated with hypergammaglobulinemia (e.g.,AIDS, autoimmune diseases, and some immunodeficiencies). In otherspecific embodiments, the present invention encompasses methods andcompositions for detecting, diagnosing and/or prognosing diseases ordisorders associated with hypogammaglobulinemia (e.g., animmunodeficiency).

[0346] Immunodeficiencies that may be detected, diagnosed, prognosed, ormonitored using the antibodies of the invention include, but are notlimited to, severe combined immunodeficiency (SCID)-X linked,SCID-autosomal, adenosine deaminase deficiency (ADA deficiency),X-linked agammaglobulinemia (XLA), Bruton's disease, congenitalagammaglobulinemia, X-linked infantile agammaglobulinemia, acquiredagammaglobulinemia, adult onset agammaglobulinemia, late-onsetagammaglobulinemia, dysgammaglobulinemia, hypogammaglobulinemia,transient hypogammaglobulinemia of infancy, unspecifiedhypogammaglobulinemia, agammaglobulinemia, common variableimmunodeficiency (CVID) (acquired), Wiskott-Aldrich Syndrome (WAS),X-linked immunodeficiency with hyper IgM, non X-linked immunodeficiencywith hyper IgM, selective IgA deficiency, IgG subclass deficiency (withor without IgA deficiency), antibody deficiency with normal or elevatedIgs, immunodeficiency with thymoma, Ig heavy chain deletions, kappachain deficiency, B cell lymphoproliferative disorder (BLPD), selectiveIgM immunodeficiency, recessive agammaglobulinemia (Swiss type),reticular dysgenesis, neonatal neutropenia, severe congenitalleukopenia, thymic alymphoplasia-aplasia or dysplasia withimmunodeficiency, ataxia-telangiectasia, short limbed dwarfism, X-linkedlymphoproliferative syndrome (XLP), Nezelof syndrome-combinedimmunodeficiency with Igs, purine nucleoside phosphorylase deficiency(PNP), MHC Class II deficiency (Bare Lymphocyte Syndrome) and severecombined immunodeficiency.

[0347] Elevated levels of soluble BLyS have been observed in the serumof patients with Systemic Lupus Erythematosus (SLE). In comparing thesera of 150 SLE patients with that of 38 control individuals, it wasfound that most of the SLE patients had more than 5 ng/ml of serum BLyS,more than 30% of SLE patients had levels greater than 10 ng/ml, andapproximately 10% of SLE patients had serum BLyS levels greater than 20ng/ml. In contrast, the majority of normal controls had BLyS levels lessthan 5 ng/ml, and less than 10% had levels higher than 10 ng/ml. Theelevated levels of BLyS protein in sera is present in the soluble formand has biologic activity as assayed by the ability to stimulateanti-IgM treated B cells in vitro. SLE patients with more than 15 ng/mlserum BLyS were also found to have elevated levels of anti-dsDNAantibodies compared to both normal controls and SLE patients with lessthan 5 ng/ml of serum BLyS.(unpublished data).

[0348] In addition the serum of two subgroups of patients which werepositive for anti-nuclear antibodies (ANA+) but did not meet the formalrequirements of the American College of Rheumatology (ACR) forclassification of SLE were analyzed for BLyS levels. The first subgroupof sera was ANA+ sera that came from patients who did not present withthe clinical impression of SLE. This group had only slightly elevatedlevels of BLyS (˜9 ng/ml BLyS). The second subgroup however, which wasANA+ sera from patients who presented with the clinical impression ofSLE, had significantly increased BLyS levels (˜15 ng/ml). These resultssuggest that an elevated level of BLyS precedes the formal fulfillmentof the ACR criteria. The ACR criteria are described in Tan, E. M., etal, Arthritis and Rheumatism 25:1271-1277 (1982).

[0349] Thus in specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor Systemic Lupus Erythematosus orconditions associated therewith. The invention provides for thedetection of aberrant expression of BLyS comprising: (a) assaying theexpression of BLyS in a biological sample of an individual using one ormore antibodies of the invention that immunospecifically binds to BLyS;and (b) comparing the level of BLyS with a standard level of BLyS, e.g.,in normal biological samples, whereby an increase in the assayed levelof BLyS compared to the standard level of BLyS is indicative of SLE.

[0350] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor IgA nephropathy or conditions associatedtherewith. The invention provides for the detection of aberrantexpression of BLyS comprising: (a) assaying the expression of BLyS in abiological sample of an individual using one or more antibodies of theinvention that immunospecifically binds to BLyS; and (b) comparing thelevel of BLyS with a standard level of BLyS, e.g., in normal biologicalsamples, whereby an increase in the assayed level of BLyS compared tothe standard level of BLyS is indicative of IgA nephropathy.

[0351] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor Sjögren's Syndrome or conditionsassociated therewith. The invention provides for the detection ofaberrant expression of BLyS comprising: (a) assaying the expression ofBLyS in a biological sample of an individual using one or moreantibodies of the invention that immunospecifically binds to BLyS; and(b) comparing the level of BLyS with a standard level of BLyS, e.g., innormal biological samples, whereby an increase in the assayed level ofBLyS compared to the standard level of BLyS is indicative of Sjögren'sSyndrome.

[0352] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor HIV infection or conditions associatedtherewith (e.g. AIDS). The invention provides for the detection ofaberrant expression of BLyS comprising: (a) assaying the expression ofBLyS in a biological sample of an individual using one or moreantibodies of the invention that immunospecifically binds to BLyS; and(b) comparing the level of BLyS with a standard level of BLyS, e.g., innormal biological samples, whereby an increase in the assayed level ofBLyS compared to the standard level of BLyS is indicative of HIVinfection.

[0353] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor Myasthenia Gravis or conditionsassociated therewith. The invention provides for the detection ofaberrant expression of BLyS comprising: (a) assaying the expression ofBLyS in a biological sample of an individual using one or moreantibodies of the invention that immunospecifically binds to BLyS; and(b) comparing the level of BLyS with a standard level of BLyS, e.g., innormal biological samples, whereby an increase in the assayed level ofBLyS compared to the standard level of BLyS is indicative of MyastheniaGravis.

[0354] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor idiopathic thrombocytopenic purpura (ITP)or conditions associated therewith. The invention provides for thedetection of aberrant expression of BLyS comprising: (a) assaying theexpression of BLyS in a biological sample of an individual using one ormore antibodies of the invention that immunospecifically binds to BLyS;and (b) comparing the level of BLyS with a standard level of BLyS, e.g.,in normal biological samples, whereby an increase in the assayed levelof BLyS compared to the standard level of BLyS is indicative ofidiopathic thrombocytopenic purpura (ITP).

[0355] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor hemolytic anemia or conditions associatedtherewith. The invention provides for the detection of aberrantexpression of BLyS comprising: (a) assaying the expression of BLyS in abiological sample of an individual using one or more antibodies of theinvention that immunospecifically binds to BLyS; and (b) comparing thelevel of BLyS with a standard level of BLyS, e.g., in normal biologicalsamples, whereby an increase in the assayed level of BLyS compared tothe standard level of BLyS is indicative of hemolytic anemia.

[0356] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor thyroiditis or conditions associatedtherewith. The invention provides for the detection of aberrantexpression of BLyS comprising: (a) assaying the expression of BLyS in abiological sample of an individual using one or more antibodies of theinvention that immunospecifically binds to BLyS; and (b) comparing thelevel of BLyS with a standard level of BLyS, e.g., in normal biologicalsamples, whereby an increase in the assayed level of BLyS compared tothe standard level of BLyS is indicative of thyroiditis.

[0357] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor Goodpasture's syndrome or conditionsassociated therewith. The invention provides for the detection ofaberrant expression of BLyS comprising: (a) assaying the expression ofBLyS in a biological sample of an individual using one or moreantibodies of the invention that immunospecifically binds to BLyS; and(b) comparing the level of BLyS with a standard level of BLyS, e.g., innormal biological samples, whereby an increase in the assayed level ofBLyS compared to the standard level of BLyS is indicative ofGoodpasture's syndrome.

[0358] In other specific embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor multiple sclerosis or conditionsassociated therewith. The invention provides for the detection ofaberrant expression of BLyS comprising: (a) assaying the expression ofBLyS in a biological sample of an individual using one or moreantibodies of the invention that immunospecifically binds to BLyS; and(b) comparing the level of BLyS with a standard level of BLyS, e.g., innormal biological samples, whereby an increase in the assayed level ofBLyS compared to the standard level of BLyS is indicative of multiplesclerosis.

[0359] In additional embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor Rheumatoid Arthritis. The inventionprovides for the detection of aberrant expression of BLyS comprising:(a) assaying the expression of BLyS in a biological sample (e.g., serumand synovial fluid) of an individual using one or more antibodies of theinvention that immunospecifically binds to BLyS; and (b) comparing thelevel of BLyS with a standard level of BLyS, e.g., in normal biologicalsamples, whereby an increase in the assayed level of BLyS compared tothe standard level of BLyS is indicative of Rheumatoid arthritis.

[0360] In additional embodiments, antibodies of the invention whichspecifically bind to BLyS can be used for diagnostic purposes to detect,diagnose, prognose, or monitor an immune-based rheumatologic disease,(e.g., SLE, rheumatoid arthritis, CREST syndrome (a variant ofscleroderma characterized by calcinosis, Raynaud's phenomenon,esophageal motility disorders, sclerodactyly, and telangiectasia.),Seronegative spondyloarthropathy (SpA), Polymyositis/dermatomyositis,Microscopic polyangiitis, Hepatitis C-associated arthritis, Takayasu'sarteritis, and undifferentiated connective tissue disorder). Theinvention provides for the detection of aberrant expression of BLyScomprising: (a) assaying the expression of BLyS in a biological sample(e.g., serum and synovial fluid) of an individual using one or moreantibodies of the invention that immunospecifically binds to BLyS; and(b) comparing the level of BLyS with a standard level of BLyS, e.g., innormal biological samples, whereby an increase in the assayed level ofBLyS compared to the standard level of BLyS is indicative of monitor animmune-based rheumatologic disease.

[0361] It has been observed, that serum BLyS levels inversely correlatewith nephrotic range proteinuria (>3 gm proteinuria in a 24 hour urinecollection) using a sample of 71 SLE patients (p=0.019). Proteinuria wasdetermined in 71 SLE patients within one month of phlebotomy for serumBLyS determination. Serum BLyS was classified as low, normal, or highbased on the 5^(th) through 95^(th) percentiles for normal controls.Nephrotic-range proteinuria was inversely correlated with serumNeutrokine-alpha levels. Thus, in specific embodiments, serum levels ofBLyS (determined using one or more antibodies of the present invention)in individuals diagnosed with an immune based rheumatologic disease(e.g., SLE, rheumatoid arthritis, CREST syndrome (a variant ofscleroderma characterized by calcinosis, Raynaud's phenomenon,esophageal motility disorders, sclerodactyly, and telangiectasia.),seronegative spondyloarthropathy (SpA), polymyositis/dermatomyositis,microscopic polyangiitis, hepatitis C-asociated arthritis, Takayasu'sarteritis, and undifferentiated connective tissue disorder) may be usedto determine, diagnose, prognose, or monitor the severity of certainaspects or symptoms of the disease, such as nephrotic-range proteinuria.

[0362] In another specific embodiment, antibodies of the invention areused to diagnose, prognose, treat, or prevent conditions associated withCVID, including, but not limited to, conditions associated with acuteand recurring infections (e.g., pneumonia, bronchitis, sinusitis, otitismedia, sepsis, meningitis, septic arthritis, and osteomyelitis), chroniclung disease, autoimmunity, granulomatous disease, lymphoma, cancers(e.g., cancers of the breast, stomach, colon, mouth, prostate, lung,vagina, ovary, skin, and melanin forming cells (i.e. melanoma),inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis,and ulcerative proctitis), malabsorption, Hodgkin's disease, andWaldenstrom's macroglobulinemia.

[0363] The invention provides a diagnostic assay for diagnosing orprognosing a disease or disorder, comprising: (a) assaying for the levelof BLyS in a biological sample of an individual using one or moreantibodies of the invention that immunospecifically bind to BLyS; and(b) comparing the level of BLyS with a standard BLyS level, e.g., in abiological sample from a patient without the disease or disorder,whereby an increase or decrease in the assayed BLyS level compared tothe standard level of BLyS is indicative of a particular disease ordisorder. With respect to cancer, the presence of a relatively highamount of BLyS in biopsied tissue from an individual may indicate apredisposition for the development of the disease, or may provide ameans for detecting the disease prior to the appearance of actualclinical symptoms. A more definitive diagnosis of this type may allowhealth professionals to employ preventative measures or aggressivetreatment earlier thereby preventing the development or furtherprogression of the cancer.

[0364] In specific embodiments, the presence of a relatively high amountof membrane-bound BLyS in a biological sample is indicative of monocyticcell related leukemias or lymphomas, such as, for example acutemyelogenous leukemia and/or the severity thereof.

[0365] In other specific embodiments, the presence of a relatively highamount of BLyS receptor in a biological sample (as determined usingantibodies of the invention that bind to soluble BLyS, but do notinhibit BLyS/BLyS receptor binding) is indicative of B cell relatedleukemias or lymphomas (e.g., chronic lymphocytic leukemia, multiplemyeloma, non-Hodgkin's lymphoma, and Hodgkin's disease), and/or theseverity thereof.

[0366] In specific embodiments, the invention provides a diagnosticassay for diagnosing or prognosing Systemic Lupus Erythematosus,comprising: (a) assaying for the level of BLyS in a biological sample ofan individual using one or more antibodies of the invention thatimmunospecifically bind to BLyS; and (b) comparing the level of BLySwith a standard BLyS level, e.g., in a biological sample from a patientwithout Systemic Lupus Erythematosus, whereby an increase in the assayedBLyS level compared to the standard level of BLyS is indicative ofSystemic Lupus Erythematosus.

[0367] In specific embodiments, the invention provides a diagnosticassay for diagnosing or prognosing a Rheumatoid Arthritis, comprising:(a) assaying for the level of BLyS in a biological sample of anindividual using one or more antibodies of the invention thatimmunospecifically bind to BLyS; and (b) comparing the level of BLySwith a standard BLyS level, e.g., in a biological sample from a patientwithout Rheumatoid Arthritis, whereby an increase or decrease in theassayed BLyS level compared to the standard level of BLyS is indicativeof Rheumatoid Arthritis.

[0368] The invention provides a diagnostic assay for diagnosing orprognosing a disease or disorder, comprising: (a) assaying for the levelof BLyS receptor in cells or a tissue sample of an individual using oneor more antibodies of the invention that immunospecifically binds onlyto soluble BLyS, but does not neutralize BLyS/BLyS receptor binding; and(b) comparing the level of BLyS receptor with a standard BLyS receptorlevel, e.g., in a tissue sample from a patient without the disease ordisorder, whereby an increase or decrease in the assayed BLyS receptorlevel compared to the standard level of BLyS receptor is indicative of aparticular disease or disorder. With respect to cancer, the presence ofa relatively high amount of BLyS receptor in biopsied tissue from anindividual may indicate a predisposition for the development of thedisease, or may provide a means for detecting the disease prior to theappearance of actual clinical symptoms. A more definitive diagnosis ofthis type may allow health professionals to employ preventative measuresor aggressive treatment earlier thereby preventing the development orfurther progression of the cancer.

[0369] Antibodies of the invention (including molecules comprising, oralternatively consisting of, antibody fragments or variants thereof) canbe used to assay protein levels in a biological sample using classicalimmunohistological methods as described herein or as known to those ofskill in the art (e.g., see Jalkanen, et al., J. Cell. Biol. 101:976-985(1985); Jalkanen, et al., J. Cell. Biol. 105:3087-3096 (1987)). Otherantibody-based methods useful for detecting protein gene expressioninclude immunoassays, such as the enzyme linked immunosorbent assay(ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labelsare known in the art and include enzyme labels, such as, glucoseoxidase, alkaline phosphatase, and horseradish peroxidase;radioisotopes, such as iodine (¹²¹I, ¹²³I, ¹²⁵I, ¹³¹I), carbon (¹⁴C),sulfur (³⁵S), tritium (³H), indium (¹¹¹In, ¹¹²In, ¹¹³In, ¹¹⁵In),technetium (⁹⁹Tc, ^(99m)Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga, ⁶⁷Ga),palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine (¹⁸F),¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc, ¹⁸⁶Re,¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, and ⁹⁷Ru; luminescent labels, such as luminol; andfluorescent labels, such as fluorescein and rhodamine, and biotin.

[0370] One aspect of the invention is the detection and diagnosis of adisease or disorder associated with aberrant expression of BLyS or BLySreceptor in an animal, preferably a mammal and most preferably a human.In one embodiment, diagnosis comprises: a) administering (for example,parenterally, subcutaneously, or intraperitoneally) to a subject aneffective amount of a labeled antibody of the invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically binds to BLyS; b) waitingfor a time interval following the administering for permitting thelabeled antibody to preferentially concentrate at sites in the subjectwhere BLyS is expressed (and for unbound labeled molecule to be clearedto background level); c) determining background level; and d) detectingthe labeled antibody in the subject, such that detection of labeledantibody or fragment thereof above the background level and above orbelow the level observed in a person without the disease or disorderindicates that the subject has a particular disease or disorderassociated with aberrant expression of BLyS or BLyS receptor. Backgroundlevel can be determined by various methods including, comparing theamount of labeled molecule detected to a standard value previouslydetermined for a particular system.

[0371] It will be understood in the art that the size of the subject andthe imaging system used will determine the quantity of imaging moietyneeded to produce diagnostic images. In the case of a radioisotopemoiety, for a human subject, the quantity of radioactivity injected willnormally range from about 5 to 20 millicuries of ⁹⁹Tc. The labeledantibody will then preferentially accumulate at the location of cellswhich contain the specific protein. In vivo tumor imaging is describedin S. W. Burchiel et al., “Immunopharmacokinetics of RadiolabeledAntibodies and Their Fragments.” (Chapter 13 in Tumor Imaging: TheRadiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes,eds., Masson Publishing Inc. (1982).

[0372] Depending on several variables, including the type of label usedand the mode of administration, the time interval following theadministration for permitting the labeled molecule to preferentiallyconcentrate at sites in the subject and for unbound labeled molecule tobe cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to12 hours. In another embodiment the time interval followingadministration is 5 to 20 days or 5 to 10 days.

[0373] In an embodiment, monitoring of the disease or disorder iscarried out by repeating the method for diagnosing the disease ordisorder, for example, one month after initial diagnosis, six monthsafter initial diagnosis, one year after initial diagnosis, etc.

[0374] Presence of the labeled molecule can be detected in the patientusing methods known in the art for in vivo scanning. These methodsdepend upon the type of label used. Skilled artisans will be able todetermine the appropriate method for detecting a particular label.Methods and devices that may be used in the diagnostic methods of theinvention include, but are not limited to, computed tomography (CT),whole body scan such as position emission tomography (PET), magneticresonance imaging (MRI), and sonography.

[0375] In a specific embodiment, the molecule is labeled with aradioisotope and is detected in the patient using a radiation responsivesurgical instrument (Thurston et al., U.S. Pat. No. 5,441,050). Inanother embodiment, the molecule is labeled with a fluorescent compoundand is detected in the patient using a fluorescence responsive scanninginstrument. In another embodiment, the molecule is labeled with apositron emitting metal and is detected in the patient using positronemission-tomography. In yet another embodiment, the molecule is labeledwith a paramagnetic label and is detected in a patient using magneticresonance imaging (MRI).

[0376] Immunophenotyping

[0377] The antibodies of the invention (including molecules comprising,or alternatively consisting of, antibody fragments or variants thereof)may be utilized for immunophenotyping of cell lines and biologicalsamples by their BLyS expression or BLyS receptor expression. Varioustechniques can be utilized using antibodies, fragments, or variants ofthe invention to screen for cellular populations (i.e., immune cells,particularly monocytic cells or B-cells) expressing BLyS or BLySreceptor, and include magnetic separation using antibody-coated magneticbeads, “panning” with antibody attached to a solid matrix (i.e., plate),and flow cytometry (see, e.g., U.S. Pat. No. 5,985,660; and Morrison etal., Cell, 96:737-49 (1999)).

[0378] These techniques allow for the screening of particularpopulations of cells, such as might be found with hematologicalmalignancies (i.e., minimal residual disease (MRD) in acute leukemicpatients) and “non-self” cells in transplantations to preventGraft-versus-Host Disease (GVHD). Alternatively, these techniques allowfor the screening of hematopoietic stem and progenitor cells capable ofundergoing proliferation and/or differentiation, as might be found inhuman umbilical cord blood.

[0379] In one embodiment, antibodies of the invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) are used to identify cells of monocytic or B cellorigin.

[0380] Therapeutic Uses of Antibodies

[0381] The present invention is further directed to antibody-basedtherapies which involve administering antibodies of the invention(including molecules comprising, or alternatively consisting of,antibody fragments or variants thereof) to an animal, preferably amammal, and most preferably a human, patient for treating one or more ofthe disclosed diseases, disorders, or conditions. Therapeutic compoundsof the invention include, but are not limited to, antibodies of theinvention and nucleic acids encoding antibodies (and anti-idiotypicantibodies) of the invention as described herein. The antibodies of theinvention can be used to treat, ameliorate or prevent diseases,disorders or conditions associated with aberrant expression and/oractivity of BLyS or BLyS receptor, including, but not limited to, anyone or more of the diseases, disorders, or conditions described herein.The treatment and/or prevention of diseases, disorders, or conditionsassociated with aberrant BLyS expression and/or activity or aberrantBLyS receptor expression and/or activity includes, but is not limitedto, alleviating symptoms associated with those diseases, disorders orconditions. Antibodies of the invention may be provided inpharmaceutically acceptable compositions as known in the art or asdescribed herein.

[0382] Antibodies of the present invention (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) that function as agonists or antagonists of BLyS,preferably of BLyS-induced signal transduction, can be administered toan animal to treat, prevent or ameliorate a disease or disorderassociated with aberrant BLyS expression, lack of BLyS function,aberrant BLyS receptor expression, or lack of BLyS receptor function.For example, antibodies of the invention which disrupt the interactionbetween BLyS and its receptor may be administered to an animal to treat,prevent or ameliorate a disease or disorder associated with aberrantBLyS expression, excessive BLyS function, aberrant BLyS receptorexpression, or excessive of BLyS receptor function. Antibodies of theinvention which do not prevent BLyS from binding its receptor butinhibit or downregulate BLyS-induced signal transduction can beadministered to an animal to treat, prevent or ameliorate a disease ordisorder associated with aberrant BLyS expression, excessive BLySfunction, aberrant BLyS receptor expression, or excessive BLyS receptorfunction. In particular, antibodies of the present invention whichprevent BLyS-induced signal transduction by specifically recognizing theunbound BLyS, receptor-bound BLyS or both unbound and receptor-boundBLyS can be administered to an animal to treat, prevent or ameliorate adisease or disorder associated with aberrant BLyS expression, excessiveBLyS function, aberrant BLyS receptor expression, or excessive BLySreceptor function. The ability of an antibody of the invention toinhibit or downregulate BLyS-induced signal transduction may bedetermined by techniques described herein or otherwise known in the art.For example, BLyS-induced receptor activation and the activation ofsignaling molecules can be determined by detecting the phosphorylation(e.g., tyrosine or serine/threonine) of the receptor or a signalingmolecule by immunoprecipitation followed by western blot analysis (forexample, as described herein).

[0383] In a specific embodiment, an antibody of the present invention(including molecules comprising, or alternatively consisting of,antibody fragments or variants thereof) that inhibits or downregulatesBLyS activity by at least 95%, at least 90%, at least 85%, at least 80%,at least 75%, at least 70%, at least 60%, at least 50%, at least 45%, atleast 40%, at least 45%, at least 35%, at least 30%, at least 25%, atleast 20%, or at least 10% relative to BLyS activity in absence of theantibody is administered to an animal to treat, prevent or ameliorate adisease or disorder associated with aberrant BLyS expression, excessiveBLyS function, aberrant BLyS receptor expression, or excessive BLySreceptor function. In another embodiment, a combination of antibodies, acombination of antibody fragments, a combination of antibody variants,or a combination of antibodies, antibody fragments, and/or variants thatinhibit or downregulate BLyS activity by at least 95%, at least 90%, atleast 85%, at least 80%, at least 75%, at least 70%, at least 65%, atleast 60%, at least 55%, at least 50%, at least 45%, at least 40%, atleast 45%, at least 35%, at least 30%, at least 25%, at least 20%, or atleast 10% relative to BLyS activity in absence of said antibodies,antibody fragments, and/or antibody variants are administered to ananimal to treat, prevent or ameliorate a disease or disorder associatedwith aberrant BLyS expression, excessive BLyS function, aberrant BLySreceptor expression, or excessive BLyS receptor function.

[0384] Further, antibodies of the present invention (including moleculescomprising, or alternatively consisting of, antibody fragments orvariants thereof) which activate BLyS-induced signal transduction can beadministered to an animal to treat, prevent or ameliorate a disease ordisorder associated with aberrant BLyS expression, lack of BLySfunction, aberrant BLyS receptor expression, or lack of BLyS receptorfunction. These antibodies may potentiate or activate either all or asubset of the biological activities of BLyS-mediated receptoractivation, for example, by inducing multimerization of BLyS and/ormultimerization of the receptor. The antibodies of the invention may beadministered with or without being pre-complexed with BLyS. In aspecific embodiment, an antibody of the present invention that increasesBLyS activity by at least 5%, at least 10%, at least 15%, at least 20%,at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, or atleast 99% relative to BLyS activity in absence of the antibody isadministered to an animal to treat, prevent or ameliorate a disease ordisorder associated with aberrant BLyS expression, lack of BLySfunction, aberrant BLyS receptor expression, or lack of BLyS receptorfunction. In another embodiment, a combination of antibodies, acombination of antibody fragments, a combination of antibody variants,or a combination of antibodies, antibody fragments and/or antibodyvariants that increase BLyS activity by at least 5%, at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 99% relative to BLyS activity inabsence of the said antibodies or antibody fragments and/or antibodyvariants is administered to an animal to treat, prevent or ameliorate adisease or disorder associated with aberrant BLyS expression or lack ofBLyS function or aberrant BLyS receptor expression or lack of BLySreceptor function.

[0385] One or more antibodies of the present invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to BLyS may be usedlocally or systemically in the body as a therapeutic. The antibodies ofthis invention (including molecules comprising, or alternativelyconsisting of, antibody fragments or variants thereof) may also beadvantageously utilized in combination with other monoclonal or chimericantibodies, or with lymphokines or hematopoietic growth factors (suchas, e.g., IL-2, IL-3 and IL-7), for example, which serve to increase thenumber or activity of effector cells which interact with the antibodies.

[0386] The antibodies of the invention (including molecules comprising,or alternatively consisting of, antibody fragments or variants thereof)may be administered alone or in combination with other types oftreatments (e.g., radiation therapy, chemotherapy, hormonal therapy,immunotherapy, anti-tumor agents, anti-angiogenesis andanti-inflammatory agents). Generally, administration of products of aspecies origin or species reactivity (in the case of antibodies) that isthe same species as that of the patient is preferred. Thus, in apreferred embodiment, human antibodies, fragments, or variants, (e.g.,derivatives), or nucleic acids, are administered to a human patient fortherapy or prophylaxis.

[0387] It is preferred to use high affinity and/or potent in vivoinhibiting and/or neutralizing antibodies of the invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) that immunospecifically bind to BLyS, orpolynucleotides encoding antibodies that immunospecifically bind toBLyS, for both immunoassays directed to and therapy of disorders relatedto BLyS polynucleotides or polypeptides, including fragments thereof.Such antibodies will preferably have an affinity for BLyS and/or BLySfragments. Preferred binding affinities include those with adissociation constant or K_(D) less than or equal to 5×10⁻² M, 10⁻² M,5×10⁻³ M, 10⁻³ M, 5×10⁻⁴ M, 10⁻⁴ M, 5×10⁻⁵ M, or 10⁻⁵ M. Morepreferably, antibodies of the invention bind BLyS polypeptides orfragments or variants thereof with a dissociation constant or K_(D) lessthan or equal to 5×10⁻⁶ M, 10⁻⁶ M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, or 10⁻⁸M. Even more preferably, antibodies of the invention bind BLySpolypeptides or fragments or variants thereof with a dissociationconstant or K_(D) less than or equal to 5×10⁻⁹ M, 10⁻⁹ M, 5×10⁻¹⁰ M,10⁻¹⁰ M, 5×10⁻¹¹ M, 10⁻¹¹ M, 5×10⁻¹² M, 10⁻² M, 5×10⁻¹³M, 10⁻¹³ M,5×10⁻¹⁴ M, 10⁻¹⁴ M, 5×10⁻¹⁵ M, or 10⁻⁵ M. The invention encompassesantibodies that bind BLyS polypeptides with a dissociation constant orK_(D) that is within any one of the ranges that are between each of theindividual recited values.

[0388] In a preferred embodiment, antibodies of the invention neutralizeBLyS activity. In another preferred embodiment, antibodies of theinvention inhibit B cell proliferation.

[0389] In a preferred embodiment, antibodies of the invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) inhibit or reduce binding of the soluble form ofBLyS to a BLyS receptor. In another preferred embodiment antibodies ofthe invention inhibit or reduce B cell proliferation induced by thesoluble form of BLyS. In another preferred embodiment antibodies of theinvention inhibit or reduce immunoglobulin production induced by thesoluble form of BLyS.

[0390] In a preferred embodiment, antibodies of the invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) inhibit or reduce binding of membrane-bound BLyS toa BLyS receptor. In another preferred embodiment, antibodies of theinvention inhibit or reduce B cell proliferation induced by themembrane-bound form of BLyS. In another preferred embodiment, antibodiesof the invention inhibit or reduce immunoglobulin production induced bythe membrane bound form of BLyS.

[0391] In a preferred embodiment, antibodies of the invention (includingmolecules comprising, or alternatively consisting of, antibody fragmentsor variants thereof) inhibit or reduce binding of both the soluble andmembrane-bound forms of BLyS to a BLyS receptor. In another preferredembodiment, antibodies of the invention inhibit or reduce B cellproliferation induced by either or both forms of BLyS. In anotherpreferred embodiment, antibodies of the invention inhibit or reduceimmunoglobulin production induced by either or both forms of BLyS.

[0392] In one embodiment, the invention provides a method of deliveringantibody conjugates of the invention to targeted cells, such as, forexample, monocytic cells expressing the membrane-bound form of BLyS, orB cells expressing a BLyS receptor.

[0393] In one embodiment, the invention provides a method for thespecific delivery of antibodies and antibody conjugates of the inventionto cells by administering molecules of the invention that are associatedwith heterologous polypeptides or nucleic acids. In one example, theinvention provides a method for delivering a therapeutic protein intothe targeted cell. In another example, the invention provides a methodfor delivering a single stranded nucleic acid (e.g., antisense orribozymes) or double stranded nucleic acid (e.g., DNA that can integrateinto the cell's genome or replicate episomally and that can betranscribed) into the targeted cell.

[0394] In another embodiment, the invention provides a method for thespecific destruction of cells (e.g., the destruction of tumor cells) byadministering antibodies or antibody conjugates of the invention (e.g.,antibodies conjugated with radioisotopes, toxins, or cytotoxicprodrugs).In a specific embodiment, the invention provides a method forthe specific destruction of cells of monocytic lineage (e.g., monocyticcell related leukemias or lymphomas, such as, for example acutemyelogenous leukemia) by administering antibodies or antibody conjugatesof the invention (e.g., antibodies conjugated with radioisotopes,toxins, or cytotoxic prodrugs) that immunospecifically bind themembrane-bound form of BLyS. In another specific embodiment, theinvention provides a method for the specific destruction of cells of Bcell lineage (e.g., B cell related leukemias or lymphomas (e.g., chroniclymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma, andHodgkin's disease) by administering antibodies or antibody conjugates ofthe invention (e.g., antibodies conjugated with radioisotopes, toxins,or cytotoxic prodrugs) that bind soluble BLyS, but do not inhibit BLySbinding to a BLyS receptor on B cells.

[0395] In another preferred embodiment antibodies of the invention(including antibody fragments and variants) promote or enhance B cellproliferation induced by the soluble form of BLyS. In another preferredembodiment, antibodies of the invention (including antibody fragmentsand variants) promote or enhance B cell proliferation induced by themembrane or soluble form of APRIL. In another preferred embodimentantibodies of the invention (including antibody fragments and variants)increase or enhance immunoglobulin production induced by the solubleform of BLyS. In another preferred embodiment antibodies of theinvention (including antibody fragments and variants) increase orenhance immunoglobulin production induced by the membrane bound orsoluble form of APRIL. In another preferred embodiment antibodies of theinvention (including antibody fragments and variants) increase orenhance immunoglobulin production in response to T cell dependentimmunogens. In another preferred embodiment antibodies of the invention(including antibody fragments and variants, and anti-antibodyantibodies) increase or enhance immunoglobulin production in response toT cell independent immunogens.

[0396] In another embodiment, therapeutic or pharmaceutical compositionsof the invention are administered to an animal to treat, prevent orameliorate immune disorders. hnmune disorders include, but are notlimited to, autoimmune disorders (e.g., arthritis, graft rejection,Hashimoto's thyroiditis, insulin-dependent diabetes, lupus, idiopathicthrombocytopenic purpura, systemic lupus erythrematosus and multiplesclerosis), elective IgA deficiency, ataxia-telangiectasia, commonvariable immunodeficiency (CVID), X-linked agammaglobulinemia, severecombined immunodeficiency (SCID), Wiskott-Aldrich syndrome, idiopathichyper-eosinophilic syndrome, monocytic leukemoid reaction, monocyticleukocytosis, monocytic leukopenia, monocytopenia, monocytosis, andgraft or transplant rejection.

[0397] As discussed herein, antibodies and antibody compositions of theinvention, may be used to treat, prevent, ameliorate, diagnose orprognose various immune system-related disorders and/or conditionsassociated with these disorders, in mammals, preferably humans. Manyautoimmune disorders result from inappropriate recognition of self asforeign material by immune cells. This inappropriate recognition resultsin an immune response leading to the destruction of the host tissue.Therefore, the administration of antibody and antibody compositions ofthe invention that can inhibit an immune response, particularly theproliferation of B cells and/or the production of immunoglobulins, maybe an effective therapy in treating and/or preventing autoimmunedisorders. Thus, in preferred embodiments, antibodies and antibodycompositions of the invention are used to treat, prevent, ameliorate,diagnose and/or prognose an autoimmune disorder, or condition(s)associated with such disorder.

[0398] Autoimmune disorders and conditions associated with thesedisorders that may be treated, prevented, ameliorated, diagnosed and/orprognosed with the therapeutic and pharmaceutical compositions of theinvention include, but are not limited to, autoimmune hemolytic anemia,autoimmune neonatal thrombocytopenia, idiopathic thrombocytopeniapurpura, autoimmune neutropenia, autoimmunocytopenia, hemolytic anemia,antiphospholipid syndrome, dermatitis, gluten-sensitive enteropathy,allergic encephalomyelitis, myocarditis, relapsing polychondritis,rheumatic heart disease, glomerulonephritis (e.g., IgA nephropathy),Multiple Sclerosis, Neuritis, Uveitis Ophthalmia, Polyendocrinopathies,Purpura (e.g., Henloch-Scoenlein purpura), Reiter's Disease, Stiff-ManSyndrome, Autoimmune Pulmonary Inflammation, myocarditis, IgAglomerulonephritis, dense deposit disease, rheumatic heart disease,Guillain-Barre Syndrome, insulin dependent diabetes mellitis, andautoimmune inflammatory eye disease.

[0399] Additional autoimmune disorders and conditions associated withthese disorders that may be treated, prevented, ameliorated, diagnosedand/or prognosed with the therapeutic and pharmaceutical compositions ofthe invention include, but are not limited to, autoimmune thyroiditis,hypothyroidism (i.e., Hashimoto's thyroiditis) (often characterized,e.g., by cell-mediated and humoral thyroid cytotoxicity), systemic lupuserhythematosus (often characterized, e.g., by circulating and locallygenerated immune complexes), discoid lupus, Goodpasture's syndrome(often characterized, e.g., by anti-basement membrane antibodies),Pemphigus (often characterized, e.g., by epidermal acantholyticantibodies), Receptor autoimmunities such as, for example, (a) Graves'Disease (often characterized, e.g., by TSH receptor antibodies), (b)Myasthenia Gravis (often characterized, e.g., by acetylcholine receptorantibodies), and (c) insulin resistance (often characterized, e.g., byinsulin receptor antibodies), autoimmune hemolytic anemia (oftencharacterized, e.g., by phagocytosis of antibody-sensitized RBCs),autoimmune thrombocytopenic purpura (often characterized, e.g., byphagocytosis of antibody-sensitized platelets.

[0400] Additional autoimmune disorders and conditions associated withthese disorders that may be treated, prevented, ameliorated, diagnosedand/or prognosed with the therapeutic and pharmaceutical compositions ofthe invention include, but are not limited to, rheumatoid arthritis(often characterized, e.g., by immune complexes in joints), schlerodermawith anti-collagen antibodies (often characterized, e.g., by nucleolarand other nuclear antibodies), mixed connective tissue disease (oftencharacterized, e.g., by antibodies to extractable nuclear antigens(e.g., ribonucleoprotein)), polymyositis/dermatomyositis (oftencharacterized, e.g., by nonhistone ANA), pernicious anemia (oftencharacterized, e.g., by antiparietal cell, microsomes, and intrinsicfactor antibodies), idiopathic Addison's disease (often characterized,e.g., by humoral and cell-mediated adrenal cytotoxicity, infertility(often characterized, e.g., by antispermatozoal antibodies),glomerulonephritis (often characterized, e.g., by glomerular basementmembrane antibodies or immune complexes) such as primaryglomerulonephritis and IgA nephropathy, bullous pemphigoid (oftencharacterized, e.g., by IgG and complement in basement membrane),Sjögren's syndrome (often characterized, e.g., by multiple tissueantibodies, and/or a specific nonhistone ANA (SS-B)), diabetes millitus(often characterized, e.g., by cell-mediated and humoral islet cellantibodies), and adrenergic drug resistance (including adrenergic drugresistance with asthma or cystic fibrosis) (often characterized, e.g.,by beta-adrenergic receptor antibodies), chronic active hepatitis (oftencharacterized, e.g., by smooth muscle antibodies), primary biliarycirrhosis (often characterized, e.g., by mitchondrial antibodies), otherendocrine gland failure (often characterized, e.g., by specific tissueantibodies in some cases), vitiligo (often characterized, e.g., bymelanocyte antibodies), vasculitis (often characterized, e.g., by Ig andcomplement in vessel walls and/or low serum complement), post-MI (oftencharacterized, e.g., by myocardial antibodies), cardiotomy syndrome(often characterized, e.g., by myocardial antibodies), urticaria (oftencharacterized, e.g., by IgG and IgM antibodies to IgE), atopicdermatitis (often characterized, e.g., by IgG and IgM antibodies toIgE), asthma (often characterized, e.g., by IgG and IgM antibodies toIgE), inflammatory myopathies, and many other inflammatory,granulomatous, degenerative, and atrophic disorders.

[0401] In a preferred embodiment, therapeutic and pharmaceuticalcompositions of the invention, are used to treat, prevent, ameliorate,diagnose or prognose, a member of the group: autoimmune hemolyticanemia, as primary glomerulonephritis, IgA glomerulonephritis,Goodpasture's syndrome, idiopathic thrombocytopenia, Multiple Sclerosis,Myasthenia Gravis, Pemphigus, polymyositis/dermatomyositis, relapsingpolychondritis, rheumatoid arthritis, Sjögren's syndrome, systemic lupuserythematosus, Uveitis, vasculitis,and primary biliary cirrhosis.

[0402] In another preferred embodiment, therapeutic and pharmaceuticalcompositions of the invention, are used to treat, prevent, ameliorate,diagnose or prognose, an immune based-rheumatologic disease, such as,for example, SLE, rheumatoid arthritis, CREST syndrome (a variant ofscleroderma characterized by calcinosis, Raynaud's phenomenon,esophageal motility disorders, sclerodactyly, and telangiectasia.),Seronegative spondyloarthropathy (SpA), polymyositis/dermatomyositis,microscopic polyangiitis, hepatitis C-associated arthritis, Takayasu'sarteritis, and undifferentiated connective tissue disorder.

[0403] In a specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, rheumatoid arthritis and/ormedical conditions associated therewith.

[0404] For example, an antibody, or antibodies, of the present inventionare used to treat patients with clinical diagnosis of rheumatoidarthritis (RA). The patient treated preferably will not have a B cellmalignancy. Moreover, the patient is optionally further treated with anyone or more agents employed for treating RA such as salicylate;nonsteroidal anti-inflammatory drugs such as indomethacin,phenylbutazone, phenylacetic acid derivatives (e.g. ibuprofen andfenoprofen), naphthalene acetic acids (naproxen), pyrrolealkanoic acid(tometin), indoleacetic acids (sulindac), halogenated anthranilic acid(meclofenamate sodium), piroxicam, zomepirac and diflunisal;antimalarials such as chloroquine; gold salts; penicillamine; orimmunosuppressive agents such as methotrexate or corticosteroids indosages known for such drugs or reduced dosages. Preferably however, thepatient is only treated with an antibody, or antibodies, of the presentinvention. Antibodies of the present invention are administered to theRA patient according to a dosing schedule as described infra, which maybe readily determined by one of ordinary skill in the art. The primaryresponse is determined by the Paulus index (Paulus et al. AthritisRheum. 33:477-484 (1990)), i.e. improvement in morning stiffness, numberof painful and inflamed joints, erythrocyte sedimentation (ESR), and atleast a 2-point improvement on a 5-point scale of disease severityassessed by patient and by physician. Administration of an antibody, orantibodies, of the present invention will alleviate one or more of thesymptoms of RA in the patient treated as described above.

[0405] In a specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, amelioate, diagnose or prognose, lupus and/or medicalconditions associated therewith. Lupus-associated conditions that may betreated, prevented, ameliorated, prognosed and/or diagnosed with theantibodies and antibody compositions of the invention include, but arenot limited to, hematologic disorders (e.g., hemolytic anemia,leukopenia, lymphopenia, and thrombocytopenia), immunologic disorders(e.g., anti-DNA antibodies, and anti-Sm antibodies), rashes,photosensitivity, oral ulcers, arthritis, fever, fatigue, weight loss,serositis (e.g., pleuritus (pleurisy)), renal disorders (e.g.,nephritis), neurological disorders (e.g., seizures, peripheralneuropathy, CNS related disorders), gastroinstestinal disorders, Raynaudphenomenon, and pericarditis. In a preferred embodiment, therapeutic andpharmaceutical compositions of the invention are used to treat, prevent,ameliorate, diagnose, or prognose, renal disorders associated withsystemic lupus erythematosus. In a most preferred embodiment,therapeutic and pharmaceutical compositions of the invention are used totreat, prevent, ameliorate, diagnose, or prognose, nephritis associatedwith systemic lupus erythematosus. In another most preferred embodiment,therapeutic or pharmaceutical compositions of the invention areadministered to an animal to treat, prevent or ameliorate lupus orglomerular nephritis.

[0406] In a further specific embodiment, antibodies of the invention areused to treat, inhibit, prognose, diagnose or prevent hemolytic anemia.For example, patients diagnosed with autoimmune hemolytic anemia (AIHA),e.g., cryoglobinemia or Coombs positive anemia, are treated with anantibody, or antibodies, of the present invention. AIHA is an acquiredhemolytic anemia due to auto-antibodies that react with the patient'sred blood cells. The patient treated preferably will not have a B cellmalignancy. Further adjunct therapies (such as glucocorticoids,prednisone, azathioprine, cyclophosphamide, vinca-laden platelets orDanazol) may be combined with the antibody therapy, but preferably thepatient is treated with an antibody, or antibodies, of the presentinvention as a single-agent throughout the course of therapy. Antibodiesof the present invention are administered to the hemolytic anemiapatient according to a dosing schedule as described infra, which may bereadily determined by one of ordinary skill in the art. Overall responserate is determined based upon an improvement in blood counts, decreasedrequirement for transfusions, improved hemoglobin levels and/or adecrease in the evidence of hemolysis as determined by standard chemicalparameters. Administration of an antibody, or antibodies of the presentinvention will improve any one or more of the symptoms of hemolyticanemia in the patient treated as described above. For example, thepatient treated as described above will show an increase in hemoglobinand an improvement in chemical parameters of hemolysis or return tonormal as measured by serum lactic dehydrogenase and/or bilirubin.

[0407] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, Sjögren's Syndrome and/ormedical conditions associated therewith.

[0408] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, HIV infection and/or medicalconditions associated therewith (e.g. AIDS).

[0409] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, Myasthenia gravis and/ormedical conditions associated therewith.

[0410] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognoses IgA nephropathy and/ormedical conditions associated therewith.

[0411] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, hemolytic anemia and/ormedical conditions associated therewith.

[0412] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, thyroiditis and/or medicalconditions associated therewith.

[0413] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, Goodpasture's Syndrome and/ormedical conditions associated therewith.

[0414] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, multiple sclerosis and/ormedical conditions associated therewith.

[0415] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, chronic lymphocytic leukemia(CLL) and/or medical conditions associated therewith.

[0416] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, multiple myeloma and/ormedical conditions associated therewith.

[0417] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, Non-Hodgkin's lymphoma and/ormedical conditions associated therewith.

[0418] In another specific preferred embodiment, therapeutic andpharmaceutical compositions of the invention, are used to treat,prevent, ameliorate, diagnose or prognose, Hodgkin's disease and/ormedical conditions associated therewith.

[0419] In another specific embodiment, antibodies of the invention areused to treat, inhibit, prognose, diagnose or prevent adult immunethrombocytopenic purpura. Adult immune thrombocytopenic purpura (ITP) isa relatively rare hematologic disorder that constitutes the most commonof the immune-mediated cytopenias. The disease typically presents withsevere thrombocytopenia that may be associated with acute hemorrhage inthe presence of normal to increased megakaryocytes in the bone marrow.Most patients with ITP have an IgG antibody directed against targetantigens on the outer surface of the platelet membrane, resulting inplatelet sequestration in the spleen and accelerated reticuloendothelialdestruction of platelets (Bussell, J.B. Hematol. Oncol. Clin. North Am.(4):179 (1990)). A number of therapeutic interventions have been shownto be effective in the treatment of ITP. Steroids are generallyconsidered first-line therapy, after which most patients are candidatesfor intravenous immunoglobulin (IVIG), splenectomy, or other medicaltherapies including vincristine or immunosuppressive/cytotoxic agents.Up to 80% of patients with ITP initially respond to a course ofsteroids, but far fewer have complete and lasting remissions.Splenectomy has been recommended as standard second-line therapy forsteroid failures, and leads to prolonged remission in nearly 60% ofcases yet may result in reduced immunity to infection. Splenectomy is amajor surgical procedure that may be associated with substantialmorbidity (15%) and mortality (2%). IVIG has also been used as secondline medical therapy, although only a small proportion of adult patientswith ITP achieve remission. Therapeutic options that would interferewith the production of autoantibodies by activated B cells without theassociated morbidities that occur with corticosteroids and/orsplenectomy would provide an important treatment approach for aproportion of patients with ITP. Patients with clinical diagnosis of ITPare treated with an antibody, or antibodies of the present invention,optionally in combination with steroid therapy. The patient treated willnot have a B cell malignancy. Antibodies of the present invention areadministered to the RA patient according to a dosing schedule asdescribed infra, which may be readily determined by one of ordinaryskill in the art. Overall patient response rate is determined based upona platelet count determined on two consecutive occasions two weeks apartfollowing treatments as described above. See, George et al. “IdiopathicThrombocytopenic Purpura: A Practice Guideline Developed by ExplicitMethods for The American Society of Hematology”, Blood 88:3-40 (1996),expressly incorporated herein by reference.

[0420] In another embodiment, therapeutic or pharmaceutical compositionsof the invention are administered to an animal to treat, prevent orameliorate an IgE-mediated allergic reaction or histamine-mediatedallergic reaction. Examples of allergic reactions include, but are notlimited to, asthma, rhinitis, eczema, chronic urticaria, and atopicdermatitis. In another embodiment, therapeutic or pharmaceuticalcompositions of the invention are administered to an animal to treat,prevent, or ameliorate anaphylaxis, hypersensitivity to an antigenicmolecule, or blood group incompatibility. In another embodiment,therapeutic or pharmaceutical compositions of the invention areadministered to an animal to treat, prevent or ameliorate or modulateinflammation or an inflammatory disorder. Examples of chronic and acuteinflammatory disorders that may be treated prevented or ameliorated withthe therapeutic and pharmaceutical compositions of the inventioninclude, but are not limited to, chronic prostatitis, granulomatousprostatitis and malacoplakia, inflammation associated with infection(e.g., septic shock, sepsis, or systemic inflammatory response syndrome(SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis,complement-mediated hyperacute rejection, nephritis, cytokine orchemokine induced lung injury, Crohn's disease, inflammatory boweldisease, chronic and acute inflammatory pulmonary diseases, bacterialinfection, psoriasis, septicemia, cerebral malaria, arthritis,gastroenteritis, and glomerular nephritis.

[0421] In another embodiment, therapeutic or pharmaceutical compositionsof the invention are administered to an animal to treat, prevent orameliorate ischemia and arteriosclerosis. Examples of such disordersinclude, but are not limited to, reperfusion damage (e.g., in the heartand/or brain) and cardiac hypertrophy.

[0422] Therapeutic or pharmaceutical compositions of the invention, mayalso be administered to modulate blood clotting and to treat or preventblood clotting disorders, such as, for example, antibody-mediatedthrombosis (i.e., antiphospholipid antibody syndrome (APS)). Forexample, therapeutic or pharmaceutical compositions of the invention,may inhibit the proliferation and differentiation of cells involved inproducing anticardiolipin antibodies. These compositions of theinvention can be used to treat, prevent, ameliorate, diagnose, and/orprognose thrombotic related events including, but not limited to, stroke(and recurrent stroke), heart attack, deep vein thrombosis, pulmonaryembolism, myocardial infarction, coronary artery disease (e.g.,antibody-mediated coronary artery disease), thrombosis, graftreocclusion following cardiovascular surgery (e.g., coronary arterialbypass grafts, recurrent fetal loss, and recurrent cardiovascularthromboembolic events.

[0423] Therapeutic or pharmaceutical compositions of the invention, mayalso be administered to treat, prevent, or ameliorate organ rejection orgraft-versus-host disease (GVHD) and/or conditions associated therewith.Organ rejection occurs by host immune cell destruction of thetransplanted tissue through an immune response. Similarly, an immuneresponse is also involved in GVHD, but, in this case, the foreigntransplanted immune cells destroy the host tissues. The administrationof antibodies of the invention, that inhibit an immune response, may bean effective therapy in preventing organ rejection or GVHD.

[0424] In another embodiment, therapeutic or pharmaceutical compositionsof the invention are administered to an animal to treat, prevent orameliorate a disease or disorder diseases associated with increasedapoptosis including, but not limited to, AIDS, neurodegenerativedisorders (such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Retinitis pigmentosa, Cerebellar degeneration),myelodysplastic syndromes (such as aplastic anemia), ischemic injury(such as that caused by myocardial infarction, stroke and reperfusioninjury), toxin-induced liver disease (such as that caused by alcohol),septic shock, cachexia and anorexia. In another embodiment, therapeuticor pharmaceutical compositions of the invention are administered to ananimal to treat, prevent or ameliorate bone marrow failure, for example,aplastic anemia and myelodysplastic syndrome.

[0425] In another embodiment, therapeutic or pharmaceutical compositionsof the invention are administered to an animal to treat, prevent orameliorate growth, progression, and/or metastases of malignancies andproliferative disorders associated with increased cell survival, or theinhibition of apoptosis. Examples of such disorders, include, but arenot limited to, leukemia (e.g., acute leukemia such as acute lymphocyticleukemia and acute myelocytic leukemia), neoplasms, tumors (e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, andretinoblastoma), heavy chain disease, metastases, or any disease ordisorder characterized by uncontrolled cell growth.

[0426] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used to treat or prevent a disordercharacterized by hpergammagloulinemia (e.g., AIDS, autoimmune diseases,and some immunodeficiencies).

[0427] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used to treat or prevent a disordercharacterized by deficient serum immunoglobulin production, recurrentinfections, and/or immune system dysfunction. Moreover, therapeutic orpharmaceutical compositions of the invention may be used to treat orprevent infections of the joints, bones, skin, and/or parotid glands,blood-borne infections (e.g., sepsis, meningitis, septic arthritis,and/or osteomyelitis), autoimmune diseases (e.g., those disclosedherein), inflammatory disorders, and malignancies, and/or any disease ordisorder or condition associated with these infections, diseases,disorders and/or malignancies) including, but not limited to, CVID,other primary immune deficiencies, HIV disease, CLL, recurrentbronchitis, sinusitis, otitis media, conjunctivitis, pneumonia,hepatitis, meningitis, herpes zoster (e.g., severe herpes zoster),and/or pneumocystis carnii.

[0428] Therapeutic or pharmaceutical compositions of the invention ofthe invention thereof, may be used to diagnose, prognose, treat orprevent one or more of the following diseases or disorders, orconditions associated therewith: primary immuodeficiencies,immune-mediated thrombocytopenia, Kawasaki syndrome, bone marrowtransplant (e.g., recent bone marrow transplant in adults or children),chronic B-cell lymphocytic leukemia, HIV infection (e.g., adult orpediatric HIV infection), chronic inflammatory demyelinatingpolyneuropathy, and post-transfusion purpura.

[0429] Additionally, therapeutic or pharmaceutical compositions of theinvention may be used to diagnose, prognose, treat or prevent one ormore of the following diseases, disorders, or conditions associatedtherewith, Guillain-Barre syndrome, anemia (e.g., anemia associated withparvovirus B19, patients with stable multiple myeloma who are at highrisk for infection (e.g., recurrent infection), autoimmune hemolyticanemia (e.g., warm-type autoimmune hemolytic anemia), thrombocytopenia(e.g., neonatal thrombocytopenia), and immune-mediated neutropenia),transplantation (e.g., cytomegalovirus (CMV)-negative recipients ofCMV-positive organs), hypogammaglobulinemia (e.g., hypogammaglobulinemicneonates with risk factor for infection or morbidity), epilepsy (e.g.,intractable epilepsy), systemic vasculitic syndromes, myasthenia gravis(e.g., decompensation in myasthenia gravis), dermatomyositis, andpolymyositis.

[0430] Additional preferred embodiments of the invention include, butare not limited to, the use of therapeutic or pharmaceuticalcompositions of the invention in the following applications:

[0431] Administration to an animal (e.g., mouse, rat, rabbit, hamster,guinea pig, pigs, micro-pig, chicken, camel, goat, horse, cow, sheep,dog, cat, non-human primate, and human, most preferably human) to boostthe immune system to produce increased quantities of one or moreantibodies (e.g., IgG, IgA, IgM, and IgE), to induce higher affinityantibody production (e.g., IgG, IgA, IgM, and IgE), and/or to increasean immune response. In a specific nonexclusive embodiment, therapeuticor pharmaceutical compositions of the invention are administered toboost the immune system to produce increased quantities of IgG. Inanother specific nonexclusive embodiment, antibodies of the areadministered to boost the immune system to produce increased quantitiesof IgA. In another specific nonexclusive embodiment antibodies of theinvention are administered to boost the immune system to produceincreased quantities of IgM.

[0432] Administration to an animal (including, but not limited to, thoselisted above, and also including transgenic animals) incapable ofproducing functional endogenous antibody molecules or having anotherwise compromised endogenous immune system, but which is capable ofproducing human immunoglobulin molecules by means of a reconstituted orpartially reconstituted immune system from another animal (see, e.g.,published PCT Application Nos. WO98/24893, WO/9634096, WO/9633735, andWO/9110741).

[0433] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a vaccine adjuvant thatenhances immune responsiveness to specific antigen. In a specificembodiment, the vaccine is an antibody described herein. In anotherspecific embodiment, the vaccine adjuvant is a polynucleotide describedherein (e.g., an antibody polynucleotide genetic vaccine adjuvant). Asdiscussed herein, therapeutic or pharmaceutical compositions of theinvention may be administered using techniques known in the art,including but not limited to, liposomal delivery, recombinant vectordelivery, injection of naked DNA, and gene gun delivery.

[0434] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an adjuvant to enhancetumor-specific immune responses.

[0435] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an adjuvant to enhanceanti-viral immune responses. Anti-viral immune responses that may beenhanced using the compositions of the invention as an adjuvant,include, but are not limited to, virus and virus associated diseases orsymptoms described herein or otherwise known in the art. In specificembodiments, the compositions of the invention are used as an adjuvantto enhance an immune response to a virus, disease, or symptom selectedfrom the group consisting of: AIDS, meningitis, Dengue, EBV, andhepatitis (e.g., hepatitis B). In another specific embodiment, thecompositions of the invention are used as an adjuvant to enhance animmune response to a virus, disease, or symptom selected from the groupconsisting of: HIV/AIDS, Respiratory syncytial virus, Dengue, Rotavirus,Japanese B encephalitis, Influenza A and B, Parainfluenza, Measles,Cytomegalovirus, Rabies, Junin, Chikungunya, Rift Valley fever, Herpessimplex, and yellow fever. In another specific embodiment, thecompositions of the invention are used as an adjuvant to enhance animmune response to the HIV gp120 antigen.

[0436] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an adjuvant to enhanceanti-bacterial or anti-fungal immune responses. Anti-bacterial oranti-fungal immune responses that may be enhanced using the compositionsof the invention as an adjuvant, include bacteria or fingus and bacteriaor fungus associated diseases or symptoms described herein or otherwiseknown in the art. In specific embodiments, the compositions of theinvention are used as an adjuvant to enhance an immune response to abacteria or fungus, disease, or symptom selected from the groupconsisting of: tetanus, Diphtheria, botulism, and meningitis type B. Inanother specific embodiment, the compositions of the invention are usedas an adjuvant to enhance an immune response to a bacteria or fingus,disease, or symptom selected from the group consisting of: Vibriocholerae, Mycobacterium leprae, Salmonella typhi, Salmonella paratyphi,Neisseria meningitidis, Streptococcus pneumoniae, Group B streptococcus,Shigella spp., Enterotoxigenic Escherichia coli, Enterohemorrhagic E.coli, Borrelia burgdorferi, and Plasmodium (malaria).

[0437] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an adjuvant to enhanceanti-parasitic immune responses. Anti-parasitic immune responses thatmay be enhanced using the compositions of the invention as an adjuvant,include parasite and parasite associated diseases or symptoms describedherein or otherwise known in the art. In specific embodiments, thecompositions of the invention are used as an adjuvant to enhance animmune response to a parasite. In another specific embodiment, thecompositions of the invention are used as an adjuvant to enhance animmune response to Plasmodium (malaria).

[0438] In a specific embodiment, compositions of the invention may beadministered to patients as vaccine adjuvants. In a further specificembodiment, compositions of the invention may be administered as vaccineadjuvants to patients suffering from an immune-deficiency. In a furtherspecific embodiment, compositions of the invention may be administeredas vaccine adjuvants to patients suffering from HIV.

[0439] In a specific embodiment, compositions of the invention may beused to increase or enhance antigen-specific antibody responses tostandard and experimental vaccines. In a specific embodiment,compositions of the invention may be used to enhance seroconversion inpatients treated with standard and experimental vaccines. In anotherspecific embodiment, compositions of the invention may be used toincrease the repertoire of antibodies recognizing unique epitopes inresponse to standard and experimental vaccination.

[0440] In a preferred embodiment, antibodies of the invention (includingantibody fragments and variants, and anti-antibody antibodies) increaseor enhance antigen-specific antibody responses to standard andexperimental vaccines by regulating binding of the soluble form of BLySto a BLyS receptor (e.g., BCMA and TACI). In another preferredembodiment, antibodies of the invention (including antibody fragmentsand variants, and anti-antibody antibodies) increase or enhanceantigen-specific antibody responses to standard and experimentalvaccines by regulating binding of the soluble form of APRIL to an APRILreceptor (e.g., BCMA and TACI).

[0441] In a preferred embodiment, antibodies of the invention (includingantibody fragments and variants, and anti-antibody antibodies) increaseor enhance seroconversion in patients treated with standard andexperimental vaccines by regulating binding of the soluble form of BLySto BLyS receptor (e.g., BCMA and TACI). In another preferred embodiment,antibodies of the invention (including antibody fragments and variants,and anti-antibody antibodies) increase or enhance seroconversion inpatients treated with standard and experimental vaccines by regulatingbinding of the soluble form of APRIL to an APRIL receptor (e.g., BCMAand TACI).

[0442] In a preferred embodiment, antibodies of the invention (includingantibody fragments and variants, and anti-antibody antibodies) increaseor enhance the repertoire of antibodies recognizing unique epitopes inresponse to standard and experimental vaccination by regulating bindingof the soluble form of BLyS to a BLyS receptor (e.g., BCMA and TACI). Inanother preferred embodiment, antibodies of the invention (includingantibody fragments and variants, and anti-antibody antibodies) increaseor enhance the repertoire of antibodies recognizing unique epitopes inresponse to standard and experimental vaccination by regulating bindingof the soluble form of APRIL to an APRIL receptor (e.g., BCMA and TACI).

[0443] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a stimulator of B cellresponsiveness to pathogens.

[0444] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent that elevates theimmune status of an individual prior to their receipt ofimmunosuppressive therapies.

[0445] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent to induce higheraffinity antibodies.

[0446] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent to increase serumimmunoglobulin concentrations.

[0447] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent to acceleraterecovery of immunocompromised individuals.

[0448] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent to boostimmunoresponsiveness among aged populations.

[0449] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an immune system enhancerprior to, during, or after bone marrow transplant and/or othertransplants (e.g., allogeneic or xenogeneic organ transplantation). Withrespect to transplantation, compositions of the invention may beadministered prior to, concomitant with, and/or after transplantation.In a specific embodiment, compositions of the invention are administeredafter transplantation, prior to the beginning of recovery of T-cellpopulations. In another specific embodiment, compositions of theinvention are first administered after transplantation after thebeginning of recovery of T cell populations, but prior to full recoveryof B cell populations.

[0450] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent to boostimmunoresponsiveness among B cell immunodeficient individuals, such as,for example, an individual who has undergone a partial or completesplenectomy. B cell immunodeficiencies that may be ameliorated ortreated by administering the antibodies and/or compositions of theinvention include, but are not limited to, severe combinedimmunodeficiency (SCID)-X linked, SCID-autosomal, adenosine deaminasedeficiency (ADA deficiency), X-linked agammaglobulinemia (XLA), Bruton'sdisease, congenital agammaglobulinemia, X-linked infantileagammaglobulinemia, acquired agammaglobulinemia, adult onsetagammaglobulinemia, late-onset agammaglobulinemia, dysgammaglobulinemia,hypogammaglobulinemia, transient hypogammaglobulinemia of infancy,unspecified hypogammaglobulinemia, agammaglobulinemia, common variableimmunodeficiency (CVID) (acquired), Wiskott-Aldrich Syndrome (WAS),X-linked immunodeficiency with hyper IgM, non X-linked immunodeficiencywith hyper IgM, selective IgA deficiency, IgG subclass deficiency (withor without IgA deficiency), antibody deficiency with normal or elevatedIgs, immunodeficiency with thymoma, Ig heavy chain deletions, kappachain deficiency, B cell lymphoproliferative disorder (BLPD), selectiveIgM immunodeficiency, recessive agammaglobulinemia (Swiss type),reticular dysgenesis, neonatal neutropenia, severe congenitalleukopenia, thymic alymphoplasia-aplasia or dysplasia withimmunodeficiency, ataxia-telangiectasia, short limbed dwarfism, X-linkedlymphoproliferative syndrome (XLP), Nezelof syndrome-combinedimmunodeficiency with Igs, purine nucleoside phosphorylase deficiency(PNP), MHC Class II deficiency (Bare Lymphocyte Syndrome) and severecombined immunodeficiency.

[0451] In a specific embodiment, antibodies and/or compositions of theinvention are administered to treat or ameliorate selective IgAdeficiency.

[0452] In another specific embodiment, antibodies and/or compositions ofthe invention are administered to treat or ameliorateataxia-telangiectasia.

[0453] In another specific embodiment antibodies and/or compositions ofthe invention are administered to treat or ameliorate common variableimmunodeficiency.

[0454] In another specific embodiment, antibodies and/or compositions ofthe invention are administered to treat or ameliorate X-linkedagammaglobulinemia.

[0455] In another specific embodiment, antibodies and/or compositions ofthe invention are administered to treat or ameliorate severe combinedimmunodeficiency (SCID).

[0456] In another specific embodiment, antibodies and/or compositions ofthe invention are administered to treat or ameliorate Wiskott-Aldrichsyndrome.

[0457] In another specific embodiment, antibodies and/or compositions ofthe invention are administered to treat or ameliorate X-linked Igdeficiency with hyper IgM.

[0458] As an agent to boost immunoresponsiveness among individualshaving an acquired loss of B cell function. Conditions resulting in anacquired loss of B cell function that may be ameliorated or treated byadministering antibodies and/or compositions of the invention include,but are not limited to, HIV Infection, AIDS, bone marrow transplant, andB cell chronic lymphocytic leukemia (CLL).

[0459] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent to boostimmunoresponsiveness among individuals having a temporary immunedeficiency. Conditions resulting in a temporary immune deficiency thatmay be ameliorated or treated by administering antibodies and/orcompositions of the invention include, but are not limited to, recoveryfrom viral infections (e.g., influenza), conditions associated withmalnutrition, recovery from infectious mononucleosis, or conditionsassociated with stress, recovery from measles, recovery from bloodtransfusion, recovery from surgery.

[0460] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a regulator of antigenpresentation by monocytes, dendritic cells, T cells and/or B-cells. Inone embodiment, antibody polypeptides or polynucleotides enhance antigenpresentation or antagonize antigen presentation in vitro or in vivo.Moreover, in related embodiments, this enhancement or antagonization ofantigen presentation may be useful in anti-tumor treatment or tomodulate the immune system.

[0461] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a mediator of mucosal immuneresponses. The expression of BLyS on monocytes, the expression of BLySreceptor on B cells, and the responsiveness of B cells to BLyS suggeststhat it may be involved in exchange of signals between B cells andmonocytes or their differentiated progeny. This activity is in many waysanalogous to the CD40-CD154 signalling between B cells and T cells.Anti-BLyS antibodies and compositions of the invention may therefore begood regulators of T cell independent immune responses to environmentalpathogens. In particular, the unconventional B cell populations (CD5+)that are associated with mucosal sites and responsible for much of theinnate immunity in humans may respond to antibodies or compositions ofthe invention thereby enhancing or inhibiting individual's immunestatus.

[0462] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an agent to direct anindividual's immune system towards development of a humoral response(i.e. TH2) as opposed to a TH1 cellular response.

[0463] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a means to induce tumorproliferation and thus make it more susceptible to anti-neoplasticagents. For example, multiple myeloma is a slowly dividing disease andis thus refractory to virtually all anti-neoplastic regimens. If thesecells were forced to proliferate more rapidly, their susceptibilityprofile would likely change.

[0464] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a monocyte cell specificbinding protein to which specific activators or inhibitors of cellgrowth may be attached. The result would be to focus the activity ofsuch activators or inhibitors onto normal, diseased, or neoplastic Bcell populations.

[0465] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a B cell specific bindingprotein to which specific activators or inhibitors of cell growth may beattached. The result would be to focus the activity of such activatorsor inhibitors onto normal, diseased, or neoplastic B cell populations.

[0466] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a means of detecting monocyticcells by virtue of its specificity. This application may requirelabeling the protein with biotin or other agents (e.g., as describedherein) to afford a means of detection.

[0467] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a means of detecting B-lineagecells by virtue of its specificity. This application may requirelabeling the protein with biotin or other agents (e.g., as describedherein) to afford a means of detection.

[0468] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a stimulator of B cellproduction in pathologies such as AIDS, chronic lymphocyte disorderand/or Common Variable immunodeficiency.

[0469] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as part of a monocyte selectiondevice the function of which is to isolate monocytes from aheterogeneous mixture of cell types. Antibodies of the invention couldbe coupled to a solid support to which monocytes would then specificallybind. Unbound cells would be washed out and the bound cells subsequentlyeluted. A non-limiting use of this selection would be to allow purgingof tumor cells from, for example, bone marrow or peripheral blood priorto transplant.

[0470] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as part of a B cell selectiondevice the flnction of which is to isolate B cells from a heterogeneousmixture of cell types. Antibodies of the invention (that do not inhibitBLyS/BLyS Receptor interaction) binding soluble BLyS could be coupled toa solid support to which B cells would then specifically bind. Unboundcells would be washed out and the bound cells subsequently eluted. Anon-limiting use of this selection would be to allow purging of tumorcells from, for example, bone marrow or peripheral blood prior totransplant.

[0471] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a therapy for generationand/or regeneration of lymphoid tissues following surgery, trauma orgenetic defect.

[0472] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a gene-based therapy forgenetically inherited disorders resulting in immuno-incompetence such asobserved among SCID patients.

[0473] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as an antigen for the generationof antibodies to inhibit or enhance BLyS mediated responses.

[0474] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a means of activatingmonocytes/macrophages to defend against parasitic diseases that effectmonocytes such as Leishmania.

[0475] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as pretreatment of bone marrowsamples prior to transplant. Such treatment would increase B cellrepresentation and thus accelerate recovery.

[0476] In a specific embodiment, therapeutic or pharmaceuticalcompositions of the invention are used as a means of regulating secretedcytokines that are elicited by BLyS and/or BLyS receptor.

[0477] Antibody polypeptides or polynucleotides of the invention may beused to modulate IgE concentrations in vitro or in vivo.

[0478] Additionally, antibody polypeptides or polynucleotides of theinvention may be used to treat, prevent, and/or diagnose IgE-mediatedallergic reactions. Such allergic reactions include, but are not limitedto, asthma, rhinitis, and eczema.

[0479] In a specific embodiment, antibody polypeptides orpolynucleotides of the invention, are administered to treat, prevent,diagnose, and/or ameliorate selective IgA deficiency.

[0480] In another specific embodiment antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate ataxia-telangiectasia.

[0481] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate common variable immunodeficiency.

[0482] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate X-linked agammaglobulinemia.

[0483] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate severe combined immunodeficiency (SCID).

[0484] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate Wiskott-Aldrich syndrome.

[0485] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate X-linked Ig deficiency with hyper IgM. In aspecific embodiment antibody polypeptides or polynucleotides of theinvention are administered to treat, prevent, diagnose, and/orameliorate X-linked Ig deficiency with hyper IgM.

[0486] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,and/or diagnose chronic myelogenous leukemia, acute myelogenousleukemia, leukemia, hystiocytic leukemia, monocytic leukemia (e.g.,acute monocytic leukemia), leukemic reticulosis, Shilling Type monocyticleukemia, and/or other leukemias derived from monocytes and/or monocyticcells and/or tissues.

[0487] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate monocytic leukemoid reaction, as seen, forexample, with tuberculosis.

[0488] In another specific embodiment, antibody polypeptides orpolynucleotides of the invention are administered to treat, prevent,diagnose, and/or ameliorate monocytic leukocytosis, monocyticleukopenia, monocytopenia, and/or monocytosis.

[0489] In a specific embodiment, antibody polypeptides orpolynucleotides of the invention are used to treat, prevent, detect,and/or diagnose monocyte disorders and/or diseases, and/or conditionsassociated therewith.

[0490] In a specific embodiment, antibody polypeptides orpolynucleotides of the invention are used to treat, prevent, detect,and/or diagnose primary B lymphocyte disorders and/or diseases, and/orconditions associated therewith. In one embodiment, such primary Blymphocyte disorders, diseases, and/or conditions are characterized by acomplete or partial loss of humoral immunity. Primary B lymphocytedisorders, diseases, and/or conditions associated therewith that arecharacterized by a complete or partial loss of humoral immunity and thatmay be prevented, treated, detected and/or diagnosed with compositionsof the invention include, but are not limited to, X-LinkedAgammaglobulinemia (XLA), severe combined immunodeficiency disease(SCID), and selective IgA deficiency.

[0491] In a preferred embodiment antibody polypeptides orpolynucleotides of the invention are used to treat, prevent, and/ordiagnose diseases or disorders affecting or conditions associated withany one or more of the various mucous membranes of the body. Suchdiseases or disorders include, but are not limited to, for example,mucositis, mucoclasis, mucocolitis, mucocutaneous leishmaniasis (suchas, for example, American leishmaniasis, leishmaniasis americana,nasopharyngeal leishmaniasis, and New World leishmaniasis),mucocutaneous lymph node syndrome (for example, Kawasaki disease),mucoenteritis, mucoepidermoid carcinoma, mucoepidermoid tumor,mucoepithelial dysplasia, mucoid adenocarcinoma, mucoid degeneration,myxoid degeneration; myxomatous degeneration; myxomatosis, mucoid medialdegeneration (for example, cystic medial necrosis), mucolipidosis(including, for example, mucolipidosis I, mucolipidosis II,mucolipidosis III, and mucolipidosis IV), mucolysis disorders,mucomembranous enteritis, mucoenteritis, mucopolysaccharidosis (such as,for example, type I mucopolysaccharidosis (i.e., Hurler's syndrome),type IS mucopolysaccharidosis (i.e., Scheie's syndrome or type Vmucopolysaccharidosis), type II mucopolysaccharidosis (i.e., Hunter'ssyndrome), type III mucopolysaccharidosis (i.e., Sanfilippo's syndrome),type IV mucopolysaccharidosis (i.e., Morquio's syndrome), type VImucopolysaccharidosis (i.e., Maroteaux-Lamy syndrome), type VIImucopolysaccharidosis (i.e, mucopolysaccharidosis due tobeta-glucuronidase deficiency), and mucosulfatidosis),mucopolysacchariduria, mucopurulent conjunctivitis, mucopus,mucormycosis (i.e., zygomycosis), mucosal disease (i.e., bovine virusdiarrhea), mucous colitis (such as, for example, mucocolitis andmyxomembranous colitis), and mucoviscidosis (such as, for example,cystic fibrosis, cystic fibrosis of the pancreas, Clarke-Hadfieldsyndrome, fibrocystic disease of the pancreas, mucoviscidosis, andviscidosis). In a highly preferred embodiment, antibody polypeptides orpolynucleotides of the invention are used to treat, prevent, and/ordiagnose mucositis, especially as associated with chemotherapy.

[0492] In a preferred embodiment, antibody polypeptides orpolynucleotides of the invention are used to treat, prevent, and/ordiagnose diseases or disorders affecting or conditions associated withsinusitis.

[0493] An additional condition, disease or symptom that can be treated,prevented, and/or diagnosed by antibody polypeptides or polynucleotidesof the invention is osteomyelitis.

[0494] An additional condition, disease or symptom that can be treated,prevented, and/or diagnosed by antibody polypeptides or polynucleotidesof the invention is endocarditis.

[0495] All of the above described applications as they may apply toveterinary medicine.

[0496] Antibody polypeptides or polynucleotides of the invention may beused to treat, prevent, and/or diagnose diseases and disorders of thepulmonary system (e.g., bronchi such as, for example, sinopulmonary andbronchial infections and conditions associated with such diseases anddisorders and other respiratory diseases and disorders. In specificembodiments, such diseases and disorders include, but are not limitedto, bronchial adenoma, bronchial asthma, pneumonia (such as, e.g.,bronchial pneumonia, bronchopneumonia, and tuberculousbronchopneumonia), chronic obstructive pulmonary disease (COPD),bronchial polyps, bronchiectasia (such as, e.g., bronchiectasia sicca,cylindrical bronchiectasis, and saccular bronchiectasis), bronchiolaradenocarcinoma, bronchiolar carcinoma, bronchiolitis (such as, e.g.,exudative bronchiolitis, bronchiolitis fibrosa obliterans, andproliferative bronchiolitis), bronchiolo-alveolar carcinoma, bronchiticasthma, bronchitis (such as, e.g., asthmatic bronchitis, Castellani'sbronchitis, chronic bronchitis, croupous bronchitis, fibrinousbronchitis, hemorrhagic bronchitis, infectious avian bronchitis,obliterative bronchitis, plastic bronchitis, pseudomembranousbronchitis, putrid bronchitis, and verminous bronchitis), bronchocentricgranulomatosis, bronchoedema, bronchoesophageal fistula, bronchogeniccarcinoma, bronchogenic cyst, broncholithiasis, bronchomalacia,bronchomycosis (such as, e.g., bronchopulmonary aspergillosis),bronchopulmonary spirochetosis, hemorrhagic bronchitis, bronchorrhea,bronchospasm, bronchostaxis, bronchostenosis, Biot's respiration,bronchial respiration, Kussmaul respiration, Kussmaul-Kien respiration,respiratory acidosis, respiratory alkalosis, respiratory distresssyndrome of the newborn, respiratory insufficiency, respiratoryscleroma, respiratory syncytial virus, and the like.

[0497] In a specific embodiment, antibody polypeptides orpolynucleotides of the invention are used to treat, prevent, and/ordiagnose chronic obstructive pulmonary disease (COPD).

[0498] In another embodiment, antibody polypeptides or polynucleotidesof the invention are used to treat, prevent, and/or diagnose fibrosesand conditions associated with fibroses, including, but not limited to,cystic fibrosis (including such fibroses as cystic fibrosis of thepancreas, Clarke-Hadfield syndrome, fibrocystic disease of the pancreas,mucoviscidosis, and viscidosis), endomyocardial fibrosis, idiopathicretroperitoneal fibrosis, leptomeningeal fibrosis, mediastinal fibrosis,nodular subepidermal fibrosis, pericentral fibrosis, perimuscularfibrosis, pipestem fibrosis, replacement fibrosis, subadventitialfibrosis, and Symmers' clay pipestem fibrosis.

[0499] In another embodiment, therapeutic or pharmaceutical compositionsof the invention are administered to an animal to treat, prevent orameliorate infectious diseases. Infectious diseases include diseasesassociated with yeast, fungal, viral and bacterial infections. Virusescausing viral infections which can be treated or prevented in accordancewith this invention include, but are not limited to, retroviruses (e.g.,human T-cell lymphotrophic virus (HTLV) types I and II and humanimmunodeficiency virus (HIV)), herpes viruses (e.g., herpes simplexvirus (HSV) types I and II, Epstein-Barr virus, HHV6-HHV8, andcytomegalovirus), arenavirues (e.g., lassa fever virus), paramyxoviruses(e.g., morbillivirus virus, human respiratory syncytial virus, mumps,and pneumovirus), adenoviruses, bunyaviruses (e.g., hantavirus),comaviruses, filoviruses (e.g., Ebola virus), flaviviruses (e.g.,hepatitis C virus (HCV), yellow fever virus, and Japanese encephalitisvirus), hepadnaviruses (e.g., hepatitis B viruses (HBV)),orthomyoviruses (e.g., influenza viruses A, B and C), papovaviruses(e.g., papillomavirues), picomaviruses (e.g., rhinoviruses,enteroviruses and hepatitis A viruses), poxviruses, reoviruses (e.g.,rotavirues), togaviruses (e.g., rubella virus), rhabdoviruses (e.g.,rabies virus). Microbial pathogens causing bacterial infections include,but are not limited to, Streptococcus pyogenes, Streptococcuspneumoniae, Neisseria gonorrhoea, Neisseria meningitidis,Corynebacterium diphtheriae, Clostridium botulinum, Clostridiumperfringens, Clostridium tetani, Haemophilus influenzae, Klebsiellapneumoniae, Klebsiella ozaenae, Klebsiella rhinoscleromotis,Staphylococcus aureus, Vibrio cholerae, Escherichia coli, Pseudomonasaeruginosa, Campylobacter (Vibrio) fetus, Campylobacter jejuni,Aeromonas hydrophila, Bacillus cereus, Edwardsiella tarda, Yersiniaenterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Shigelladysenteriae, Shigella flexneri, Shigella sonnei, Salmonella typhimurium,Treponema pallidum, Treponema pertenue, Treponema carateneum, Borreliavincentii, Borrelia burgdorferi, Leptospira icterohemorrhagiae,Mycobacterium tuberculosis, Toxoplasma gondii, Pneumocystis carinii,Francisella tularensis, Brucella abortus, Brucella suis, Brucellamelitensis, Mycoplasma spp., Rickettsia prowazeki, Rickettsiatsutsugumushi, Chlamydia spp., and Helicobacter pylori.

[0500] Gene Therapy

[0501] In a specific embodiment, nucleic acids comprising sequencesencoding antibodies or functional derivatives thereof, are administeredto treat, inhibit or prevent a disease or disorder associated withaberrant expression and/or activity of BLyS and/or its receptor, by wayof gene therapy. Gene therapy refers to therapy performed by theadministration to a subject of an expressed or expressible nucleic acid.In this embodiment of the invention, the nucleic acids produce theirencoded protein that mediates a therapeutic effect.

[0502] Any of the methods for gene therapy available in the art can beused according to the present invention. Exemplary methods are describedbelow.

[0503] For general reviews of the methods of gene therapy, see Goldspielet al., Clinical Pharmacy 12:488-505 (1993); Wu and Wu, Biotherapy3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596(1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson,Ann. Rev. Biochem. 62:191-217 (1993); May, TIBTECH 11(5):155-215 (1993).Methods commonly known in the art of recombinant DNA technology whichcan be used are described in Ausubel et al. (eds.), Current Protocols inMolecular Biology, John Wiley & Sons, NY (1993); and Kriegler, GeneTransfer and Expression, A Laboratory Manual, Stockton Press, NY (1990).

[0504] In a preferred aspect, a composition of the invention comprises,or alternatively consists of, nucleic acids encoding an antibody, saidnucleic acids being part of an expression vector that expresses theantibody or fragments or chimeric proteins or heavy or light chainsthereof in a suitable host. In particular, such nucleic acids havepromoters, preferably heterologous promoters, operably linked to theantibody coding region, said promoter being inducible or constitutive,and, optionally, tissue-specific. In another particular embodiment,nucleic acid molecules are used in which the antibody coding sequencesand any other desired sequences are flanked by regions that promotehomologous recombination at a desired site in the genome, thus providingfor intrachromosomal expression of the antibody encoding nucleic acids(Koller and Smithies, Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989);Zijlstra et al., Nature 342:435-438 (1989). In specific embodiments, theexpressed antibody molecule is an scFv; alternatively, the nucleic acidsequences include sequences encoding both the heavy and light chains, orfragments or variants thereof, of an antibody.

[0505] Delivery of the nucleic acids into a patient may be eitherdirect, in which case the patient is directly exposed to the nucleicacid or nucleic acid- carrying vectors, or indirect, in which case,cells are first transformed with the nucleic acids in vitro, thentransplanted into the patient. These two approaches are known,respectively, as in vivo or ex vivo gene therapy.

[0506] In a specific embodiment, the nucleic acid sequences are directlyadministered in vivo, where it is expressed to produce the encodedproduct. This can be accomplished by any of numerous methods known inthe art, e.g., by constructing them as part of an appropriate nucleicacid expression vector and administering it so that they becomeintracellular, e.g., by infection using defective or attenuatedretrovirals or other viral vectors (see U.S. Pat. No. 4,980,286), or bydirect injection of naked DNA, or by use of microparticle bombardment(e.g., a gene gun; Biolistic, Dupont), or coating with lipids orcell-surface receptors or transfecting agents, encapsulation inliposomes, microparticles, or microcapsules, or by administering them inlinkage to a peptide which is known to enter the nucleus, byadministering it in linkage to a ligand subject to receptor-mediatedendocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987))(which can be used to target cell types specifically expressing thereceptors), etc. In another embodiment, nucleic acid-ligand complexescan be formed in which the ligand comprises a fusogenic viral peptide todisrupt endosomes, allowing the nucleic acid to avoid lysosomaldegradation. In yet another embodiment, the nucleic acid can be targetedin vivo for cell specific uptake and expression, by targeting a specificreceptor (see, e.g., PCT Publications WO 92/06 180; WO 92/22635;W092/203 16; W093/14188, WO 93/20221). Alternatively, the nucleic acidcan be introduced intracellularly and incorporated within host cell DNAfor expression, by homologous recombination (Koller and Smithies, Proc.Natl. Acad. Sci. USA 86:8932-8935 (1989); Zijlstra et al., Nature342:435-438 (1989)).

[0507] In a specific embodiment, viral vectors that contains nucleicacid sequences encoding an antibody of the invention or fragments orvariants thereof are used. For example, a retroviral vector can be used(see Miller et al., Meth. Enzymol. 217:581-599 (1993)). These retroviralvectors contain the components necessary for the correct packaging ofthe viral genome and integration into the host cell DNA. The nucleicacid sequences encoding the antibody to be used in gene therapy arecloned into one or more vectors, which facilitates delivery of the geneinto a patient. More detail about retroviral vectors can be found inBoesen et al., Biotherapy 6:291-302 (1994), which describes the use of aretroviral vector to deliver the mdr 1 gene to hematopoietic stem cellsin order to make the stem cells more resistant to chemotherapy. Otherreferences illustrating the use of retroviral vectors in gene therapyare: Clowes et al., J. Clin. Invest. 93:644-651(1994); Klein et al.,Blood 83:1467-1473 (1994); Salmons and Gunzberg, Human Gene Therapy4:129-141 (1993); and Grossman and Wilson, Curr. Opin. in Genetics andDevel. 3:110-114 (1993).

[0508] Adenoviruses are other viral vectors that can be used in genetherapy. Adenoviruses are especially attractive vehicles for deliveringgenes to respiratory epithelia. Adenoviruses naturally infectrespiratory epithelia where they cause a mild disease. Other targets foradenovirus-based delivery systems are liver, the central nervous system,endothelial cells, and muscle. Adenoviruses have the advantage of beingcapable of infecting non-dividing cells. Kozarsky and Wilson, CurrentOpinion in Genetics and Development 3:499-503 (1993) present a review ofadenovirus-based gene therapy. Bout et al., Human Gene Therapy 5:3-10(1994) demonstrated the use of adenovirus vectors to transfer genes tothe respiratory epithelia of rhesus monkeys. Other instances of the useof adenoviruses in gene therapy can be found in Rosenfeld et al.,Science 252:431-434 (1991); Rosenfeld et al., Cell 68:143-155 (1992);Mastrangeli et al., J. Clin. Invest. 91:225-234 (1993); PCT PublicationW094/12649; and Wang, et al., Gene Therapy 2:775-783 (1995). In apreferred embodiment, adenovirus vectors are used.

[0509] Adeno-associated virus (AAV) has also been proposed for use ingene therapy (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300(1993); U.S. Pat. No. 5,436,146).

[0510] Another approach to gene therapy involves transferring a gene tocells in tissue culture by such methods as electroporation, lipofection,calcium phosphate mediated transfection, or viral infection. Usually,the method of transfer includes the transfer of a selectable marker tothe cells. The cells are then placed under selection to isolate thosecells that have taken up and are expressing the transferred gene. Thosecells are then delivered to a patient.

[0511] In this embodiment, the nucleic acid is introduced into a cellprior to administration in vivo of the resulting recombinant cell. Suchintroduction can be carried out by any method known in the art,including but not limited to transfection, electroporation,microinjection, infection with a viral or bacteriophage vectorcontaining the nucleic acid sequences, cell fusion, chromosome-mediatedgene transfer, microcell-mediated gene transfer, spheroplast fusion,etc. Numerous techniques are known in the art for the introduction offoreign genes into cells (see, e.g., Loeffler and Behr, Meth. Enzymol.217:599-618 (1993); Cohen et al., Meth. Enzymol. 217:618-644 (1993);Clin. Pharma. Ther. 29:69-92m (1985)) and may be used in accordance withthe present invention, provided that the necessary developmental andphysiological functions of the recipient cells are not disrupted. Thetechnique should provide for the stable transfer of the nucleic acid tothe cell, so that the nucleic acid is expressible by the cell andpreferably heritable and expressible by its cell progeny.

[0512] The resulting recombinant cells can be delivered to a patient byvarious methods known in the art. Recombinant blood cells (e.g.,hematopoietic stem or progenitor cells) are preferably administeredintravenously. The amount of cells envisioned for use depends on thedesired effect, patient state, etc., and can be determined by oneskilled in the art.

[0513] Cells into which a nucleic acid can be introduced for purposes ofgene therapy encompass any desired, available cell type, and include butare not limited to epithelial cells, endothelial cells, keratinocytes,fibroblasts, muscle cells, hepatocytes; blood cells such as Tlymphocytes, B lymphocytes, monocytes, macrophages, neutrophils,eosinophils, megakaryocytes, granulocytes; various stem or progenitorcells, in particular hematopoietic stem or progenitor cells, e.g., asobtained from bone marrow, umbilical cord blood, peripheral blood, fetalliver, etc.

[0514] In a preferred embodiment, the cell used for gene therapy isautologous to the patient.

[0515] In an embodiment in which recombinant cells are used in genetherapy, nucleic acid sequences encoding an antibody or fragment thereofare introduced into the cells such that they are expressible by thecells or their progeny, and the recombinant cells are then administeredin vivo for therapeutic effect. In a specific embodiment, stem orprogenitor cells are used. Any stem and/or progenitor cells which can beisolated and maintained in vitro can potentially be used in accordancewith this embodiment of the present invention (see e.g. PCT PublicationWO 94/08598; Stemple and Anderson, Cell 7 1:973-985 (1992); Rheinwald,Meth. Cell Bio. 21A:229 (1980); and Pittelkow and Scott, Mayo ClinicProc. 61:771 (1986)).

[0516] In a specific embodiment, the nucleic acid to be introduced forpurposes of gene therapy comprises an inducible promoter operably linkedto the coding region, such that expression of the nucleic acid iscontrollable by controlling the presence or absence of the appropriateinducer of transcription.

[0517] Demonstration of Therapeutic or Prophylactic Utility of aComposition

[0518] The compounds of the invention are preferably tested in vitro,and then in vivo for the desired therapeutic or prophylactic activity,prior to use in humans. For example, in vitro assays which can be usedto determine whether administration of a specific antibody orcomposition of the present invention is indicated, include in vitro cellculture assays in which a patient tissue sample is grown in culture, andexposed to or otherwise administered an antibody or composition of thepresent invention, and the effect of such an antibody or composition ofthe present invention upon the tissue sample is observed. In variousspecific embodiments, in vitro assays can be carried out withrepresentative cells of cell types involved in a patient's disorder, todetermine if an antibody or composition of the present invention has adesired effect upon such cell types. Preferably, the antibodies orcompositions of the invention are also tested in in vitro assays andanimal model systems prior to administration to humans.

[0519] Antibodies or compositions of the present invention for use intherapy can be tested for their toxicity in suitable animal modelsystems, including but not limited to rats, mice, chicken, cows,monkeys, and rabbits. For in vivo testing of an antibody orcomposition's toxicity any animal model system known in the art may beused.

[0520] Efficacy in treating or preventing viral infection may bedemonstrated by detecting the ability of an antibody or composition ofthe invention to inhibit the replication of the virus, to inhibittransmission or prevent the virus from establishing itself in its host,or to prevent, ameliorate or alleviate the symptoms of disease aprogression. The treatment is considered therapeutic if there is, forexample, a reduction in viral load, amelioration of one or moresymptoms, or a decrease in mortality and/or morbidity followingadministration of an antibody or composition of the invention.

[0521] Antibodies or compositions of the invention can be tested for theability to induce the expression of cytokines such as IFN-γ, bycontacting cells, preferably human cells, with an antibody orcomposition of the invention or a control antibody or controlcomposition and determining the ability of the antibody or compositionof the invention to induce one or more cytokines. Techniques known tothose of skill in the art can be used to measure the level of expressionof cytokines. For example, the level of expression of cytokines can bemeasured by analyzing the level of RNA of cytokines by, for example,RT-PCR and Northern blot analysis, and by analyzing the level ofcytokines by, for example, immunoprecipitation followed by western blotanalysis and ELISA. In a preferred embodiment, a compound of theinvention is tested for its ability to induce the expression of IFN-γζ

[0522] Antibodies or compositions of the invention can be tested fortheir ability to modulate the biological activity of immune cells bycontacting immune cells, preferably human immune cells (e.g., T-cells,B-cells, and Natural Killer cells), with an antibody or composition ofthe invention or a control compound and determining the ability of theantibody or composition of the invention to modulate (i.e, increase ordecrease) the biological activity of immune cells. The ability of anantibody or composition of the invention to modulate the biologicalactivity of immune cells can be assessed by detecting the expression ofantigens, detecting the proliferation of immune cells (i.e., B-cellproliferation), detecting the activation of signaling molecules,detecting the effector function of immune cells, or detecting thedifferentiation of immune cells. Techniques known to those of skill inthe art can be used for measuring these activities. For example,cellular proliferation can be assayed by ³H-thymidine incorporationassays and trypan blue cell counts. Antigen expression can be assayed,for example, by immunoassays including, but not limited to, competitiveand non-competitive assay systems using techniques such as westernblots, immunohistochemistry radioimmunoassays, ELISA (enzyme linkedimmunosorbent assay), “sandwich” immunoassays, immunoprecipitationassays, precipitin reactions, gel diffusion precipitin reactions,immunodiffusion assays, agglutination assays, complement-fixationassays, immunoradiometric assays, fluorescent immunoassays, protein Aimmunoassays and FACS analysis. The activation of signaling moleculescan be assayed, for example, by kinase assays and electrophoretic shiftassays (EMSAs). In a preferred embodiment, the ability of an antibody orcomposition of the invention to induce B-cell proliferation is measured.In another preferred embodiment, the ability of an antibody orcomposition of the invention to modulate immunoglobulin expression ismeasured.

[0523] Antibodies or compositions of the invention can be tested fortheir ability to reduce tumor formation in in vitro, ex vivo and in vivoassays. Antibodies or compositions of the invention can also be testedfor their ability to inhibit viral replication or reduce viral load inin vitro and in vivo assays. Antibodies or compositions of the inventioncan also be tested for their ability to reduce bacterial numbers in invitro and in vivo assays known to those of skill in the art. Antibodiesor compositions of the invention can also be tested for their ability toalleviate of one or more symptoms associated with cancer, an immunedisorder (e.g., an inflammatory disease), a neurological disorder or aninfectious disease. Antibodies or compositions of the invention can alsobe tested for their ability to decrease the time course of theinfectious disease. Further, antibodies or compositions of the inventioncan be tested for their ability to increase the survival period ofanimals suffering from disease or disorder, including cancer, an immunedisorder or an infectious disease. Techniques known to those of skill inthe art can be used to analyze the function of the antibodies orcompositions of the invention in vivo.

[0524] Therapeutic/Prophylactic Compositions and Administration

[0525] The invention provides methods of treatment, inhibition andprophylaxis by administration to a subject of an effective amount ofantibody (or fragment or variant thereof) or pharmaceutical compositionof the invention, preferably an antibody of the invention. In apreferred aspect, an antibody or fragment or variant thereof issubstantially purified (i.e., substantially free from substances thatlimit its effect or produce undesired side-effects). The subject ispreferably an animal, including but not limited to, animals such ascows, pigs, horses, chickens, cats, dogs, etc., and is preferably amammal, and most preferably a human.

[0526] Formulations and methods of administration that can be employedwhen the compound comprises a nucleic acid or an immunoglobulin aredescribed above; additional appropriate formulations and routes ofadministration can be selected from among those described herein below.

[0527] Various delivery systems are known and can be used to administerantibody or fragment or variant thereof of the invention, e.g.,encapsulation in liposomes, microparticles, microcapsules, recombinantcells capable of expressing the antibody or antibody fragment,receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem.262:4429-4432 (1987)), construction of a nucleic acid as part of aretroviral or other vector, etc. Methods of introduction include, butare not limited to, intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, and oral routes. Thecompositions may be administered by any convenient route, for example byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa,etc.) and may be administered together with other biologically activeagents. Administration can be systemic or local. In addition, it may bedesirable to introduce the pharmaceutical compositions of the inventioninto the central nervous system by any suitable route, includingintraventricular and intrathecal injection; intraventricular injectionmay be facilitated by an intraventricular catheter, for example,attached to a reservoir, such as an Onimaya reservoir. Pulnonaryadministration can also be employed, e.g., by use of an inhaler ornebulizer, and formulation with an aerosolizing agent.

[0528] In a specific embodiment, it may be desirable to administer thepharmaceutical compositions of the invention locally to the area in needof treatment; this may be achieved by, for example, and not by way oflimitation, local infusion during surgery, topical application, e.g., inconjunction with a wound dressing after surgery, by injection, by meansof a catheter, by means of a suppository, or by means of an implant,said implant being of a porous, non-porous, or gelatinous material,including membranes, such as sialastic membranes, or fibers. Preferably,when administering a protein, including an antibody, of the invention,care must be taken to use materials to which the protein does notabsorb.

[0529] In another embodiment, the composition can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al, in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp. 3 17-327; see generallyibid.).

[0530] In yet another embodiment, the composition can be delivered in acontrolled release system. In one embodiment, a pump may be used (seeLanger, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:20 1 (1987);Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989)). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem.23:61 (1983); see also Levy et al., Science 228:190 (1985); During etal, Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105(1989)). In yet another embodiment, a controlled release system can beplaced in proximity of the therapeutic target, i.e., the brain, thusrequiring only a fraction of the systemic dose (see, e.g., Goodson, inMedical Applications of Controlled Release, supra, vol. 2, pp. 115-138(1984)).

[0531] Other controlled release systems are discussed in the review byLanger (Science 249:1527-1533 (1990)).

[0532] In a specific embodiment where the composition of the inventionis a nucleic acid encoding a protein, the nucleic acid can beadministered in vivo to promote expression of its encoded protein, byconstructing it as part of an appropriate nucleic acid expression vectorand administering it so that it becomes intracellular, e.g., by use of aretroviral vector (see U.S. Pat. No. 4,980,286), or by direct injection,or by use of microparticle bombardment (e.g., a gene gun; Biolistic,Dupont), or coating with lipids or cell-surface receptors ortransfecting agents, or by administering it in linkage to ahomeobox-like peptide which is known to enter the nucleus (see e.g.,Joliot et al., Proc. Natl. Acad. Sci. USA 88:1864-1868 (1991)), etc.Alternatively, a nucleic acid can be introduced intracellularly andincorporated within host cell DNA for expression, by homologousrecombination.

[0533] The present invention also provides pharmaceutical compositions.Such compositions comprise a therapeutically effective amount of anantibody or a fragment thereof, and a pharmaceutically acceptablecarrier. In a specific embodiment, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans. The term “carrier” refers to a diluent, adjuvant, excipient, orvehicle with which the therapeutic is administered. Such pharmaceuticalcarriers can be sterile liquids, such as water and oils, including thoseof petroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water is a preferredcarrier when the pharmaceutical composition is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions. Suitable pharmaceutical excipients include starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The composition, if desired, can also contain minor amounts ofwetting or emulsifying agents, or pH buffering agents. Thesecompositions can take the form of solutions, suspensions, emulsion,tablets, pills, capsules, powders, sustained-release formulations andthe like. The composition can be formulated as a suppository, withtraditional binders and carriers such as triglycerides. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Examples of suitable pharmaceutical carriersare described in “Remington's Pharmaceutical Sciences” by E.W. Martin.Such compositions will contain a therapeutically effective amount of theantibody or fragment thereof, preferably in purified form, together witha suitable amount of carrier so as to provide the form for properadministration to the patient. The formulation should suit the mode ofadministration.

[0534] In a preferred embodiment, the composition is formulated inaccordance with routine procedures as a pharmaceutical compositionadapted for intravenous administration to human beings. Typically,compositions for intravenous administration are solutions in sterileisotonic aqueous buffer. Where necessary, the composition may alsoinclude a solubilizing agent and a local anesthetic such as lignocanmeto ease pain at the site of the injection. Generally, the ingredientsare supplied either separately or mixed together in unit dosage form,for example, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampoule or sachette indicatingthe quantity of active agent. Where the composition is to beadministered by infusion, it can be dispensed with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where thecomposition is administered by injection, an ampoule of sterile waterfor injection or saline can be provided so that the ingredients may bemixed prior to administration.

[0535] The compositions of the invention can be formulated as neutral orsalt forms. Pharmaceutically acceptable salts include those formed withanions such as those derived from hydrochloric, phosphoric, acetic,oxalic, tartaric acids, etc., and those formed with cations such asthose derived from sodium, potassium, ammonium, calcium, ferrichydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol,histidine, procaine, etc.

[0536] The amount of the composition of the invention which will beeffective in the treatment, inhibition and prevention of a disease ordisorder associated with aberrant expression and/or activity of apolypeptide of the invention can be determined by standard clinicaltechniques. In addition, in vitro assays may optionally be employed tohelp identify optimal dosage ranges. The precise dose to be employed inthe formulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided accordingto the judgment of the practitioner and each patient's circumstances.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

[0537] For antibodies, the dosage administered to a patient is typically0.1 mg/kg to 100 mg/kg of the patient's body weight. Preferably, thedosage administered to a patient is between 0.1 mg/kg and 20 mg/kg ofthe patient's body weight, more preferably 1 mg/kg to 10 mg/kg of thepatient's body weight. Generally, human antibodies have a longerhalf-life within the human body than antibodies from other species dueto the immune response to the foreign polypeptides. Thus, lower dosagesof human antibodies and less frequent administration is often possible.Further, the dosage and frequency of administration of therapeutic orpharmaceutical compositions of the invention may be reduced by enhancinguptake and tissue penetration (e.g., into the brain) of the antibodiesby modifications such as, for example, lipidation.

[0538] The antibodies and antibody compositions of the invention may beadministered alone or in combination with other adjuvants. Adjuvantsthat may be administered with the antibody and antibody compositions ofthe invention include, but are not limited to, alum, alum plusdeoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genentech, Inc.),BCG, and MPL. In a specific embodiment, antibody and antibodycompositions of the invention are administered in combination with alum.In another specific embodiment, antibody and antibody compositions ofthe invention are administered in combination with QS-21. Furtheradjuvants that may be administered with the antibody and antibodycompositions of the invention include, but are not limited to,Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18,CRL1005, Aluminum salts, MF-59, and Virosomal adjuvant technology.Vaccines that may be administered with the antibody and antibodycompositions of the invention include, but are not limited to, vaccinesdirected toward protection against MMR (measles, mumps, rubella), polio,varicella, tetanus/diptheria, hepatitis A, hepatitis B, haemophilusinfluenzae B, whooping cough, pneumonia, influenza, Lyme's Disease,rotavirus, cholera, yellow fever, Japanese encephalitis, poliomyelitis,rabies, typhoid fever, and pertussis, and/or PNEUMOVAX-23™. Combinationsmay be administered either concomitantly, e.g., as an admixture,separately but simultaneously or concurrently; or sequentially. Thisincludes presentations in which the combined agents are administeredtogether as a therapeutic mixture, and also procedures in which thecombined agents are administered separately but simultaneously, e.g., asthrough separate intravenous lines into the same individual.Administration “in combination” further includes the separateadministration of one of the compounds or agents given first, followedby the second.

[0539] In another specific embodiment, antibody and antibodycompositions of the invention are used in combination with PNEUMOVAX-23™to treat, prevent, and/or diagnose infection and/or any disease,disorder, and/or condition associated therewith. In one embodiment,antibody and antibody compositions of the invention are used incombination with PNEUMOVAX-23™ to treat, prevent, and/or diagnose anyGram positive bacterial infection and/or any disease, disorder, and/orcondition associated therewith. In another embodiment, antibody andantibody compositions of the invention are used in combination withPNEUMOVAX-23™ to treat, prevent, and/or diagnose infection and/or anydisease, disorder, and/or condition associated with one or more membersof the genus Enterococcus and/or the genus Streptococcus. In anotherembodiment, antibody and antibody compositions of the invention are usedin any combination with PNEUMOVAX-23™ to treat, prevent, and/or diagnoseinfection and/or any disease, disorder, and/or condition associated withone or more members of the Group B streptococci. In another embodiment,antibody and antibody compositions of the invention are used incombination with PNEUMOVAX-23™ to treat, prevent, and/or diagnoseinfection and/or any disease, disorder, and/or condition associated withStreptococcus pneumoniae.

[0540] The antibody and antibody compositions of the invention may beadministered alone or in combination with other therapeutic agents,including but not limited to, chemotherapeutic agents, antibiotics,antivirals, steroidal and non-steroidal anti-inflammatories,conventional immunotherapeutic agents and cytokines. Combinations may beadministered either concomitantly, e.g., as an admixture, separately butsimultaneously or concurrently; or sequentially. This includespresentations in which the combined agents are administered together asa therapeutic mixture, and also procedures in which the combined agentsare administered separately but simultaneously, e.g., as throughseparate intravenous lines into the same individual. Administration “incombination” further includes the separate administration of one of thecompounds or agents given first, followed by the second.

[0541] In one embodiment, the antibody and antibody compositions of theinvention are administered in combination with other members of the TNFfamily. TNF, TNF-related or TNF-like molecules that may be administeredwith the antibody and antibody compositions of the invention include,but are not limited to, soluble forms of TNF-alpha, lymphotoxin-alpha(LT-alpha, also known as TNF-beta), LT-beta (found in complexheterotrimer LT-alpha2-beta), OPGL, FasL, CD27L, CD30L, CD40L, 4-1BBL,DcR3, OX40L, TNF-gamma (International Publication No. WO 96/14328),TRAIL, AIM-II (International Publication No. WO 97/34911), APRIL (J.Exp. Med. 188(6):1185-1190 (1998)), endokine-alpha (InternationalPublication No. WO 98/07880), Neutrokine-alpha (InternatioanlApplication Publication No. WO 98/18921), OPG, OX40, and nerve growthfactor (NGF), and soluble forms of Fas, CD30, CD27, CD40 and 4-IBB, TR2(International Publication No. WO 96/34095), DR3 (InternationalPublication No. WO 97/33904), DR4 (International Publication No. WO98/32856), TR5 (International Publication No. WO 98/30693), TR6(International Publication No. WO 98/30694), TR7 (InternationalPublication No. WO 98/41629), TRANK, TR9 (International Publication No.WO 98/56892), 312C2 (International Publication No. WO 98/06842), andTR12, and soluble forms CD154, CD70, and CD153.

[0542] In a preferred embodiment, the antibody and antibody compositionsof the invention are administered in combination with CD40 ligand(CD40L), a soluble form of CD40L (e.g., AVREND™), biologically activefragments, variants, or derivatives of CD40L, anti-CD40L antibodies(e.g., agonistic or antagonistic antibodies), and/or anti-CD40antibodies (e.g., agonistic or antagonistic antibodies).

[0543] In an additional embodiment, the antibody and antibodycompositions of the invention are administered alone or in combinationwith an anti-angiogenic agent(s). Anti-angiogenic agents that may beadministered with the antibody and antibody compositions of theinvention include, but are not limited to, Angiostatin (Entremed,Rockville, Md.), Troponin-1 (Boston Life Sciences, Boston, Mass.),anti-Invasive Factor, retinoic acid and derivatives thereof, paclitaxel(Taxol), Suramin, Tissue Inhibitor of Metalloproteinase-1, TissueInhibitor of Metalloproteinase-2, VEGI, Plasminogen ActivatorInhibitor-1, Plasminogen Activator Inhibitor-2, and various forms of thelighter “d group” transition metals.

[0544] Lighter “d group” transition metals include, for example,vanadium, molybdenum, tungsten, titanium, niobium, and tantalum species.Such transition metal species may form transition metal complexes.Suitable complexes of the above-mentioned transition metal speciesinclude oxo transition metal complexes.

[0545] Representative examples of vanadium complexes include oxovanadium complexes such as vanadate and vanadyl complexes. Suitablevanadate complexes include metavanadate and orthovanadate complexes suchas, for example, ammonium metavanadate, sodium metavanadate, and sodiumorthovanadate. Suitable vanadyl complexes include, for example, vanadylacetylacetonate and vanadyl sulfate including vanadyl sulfate hydratessuch as vanadyl sulfate mono- and trihydrates.

[0546] Representative examples of tungsten and molybdenum complexes alsoinclude oxo complexes. Suitable oxo tungsten complexes include tungstateand tungsten oxide complexes. Suitable tungstate complexes includeammonium tungstate, calcium tungstate, sodium tungstate dihydrate, andtungstic acid. Suitable tungsten oxides include tungsten (IV) oxide andtungsten (VI) oxide. Suitable oxo molybdenum complexes includemolybdate, molybdenum oxide, and molybdenyl complexes. Suitablemolybdate complexes include ammonium molybdate and its hydrates, sodiummolybdate and its hydrates, and potassium molybdate and its hydrates.Suitable molybdenum oxides include molybdenum (VI) oxide, molybdenum(VI) oxide, and molybdic acid. Suitable molybdenyl complexes include,for example, molybdenyl acetylacetonate. Other suitable tungsten andmolybdenum complexes include hydroxo derivatives derived from, forexample, glycerol, tartaric acid, and sugars.

[0547] A wide variety of other anti-angiogenic factors may also beutilized within the context of the present invention. Representativeexamples include, but are not limited to, platelet factor 4; protaminesulphate; sulphated chitin derivatives (prepared from queen crabshells), (Murata et al., Cancer Res. 51:22-26, 1991); SulphatedPolysaccharide Peptidoglycan Complex (SP-PG) (the function of thiscompound may be enhanced by the presence of steroids such as estrogen,and tamoxifen citrate); Staurosporine; modulators of matrix metabolism,including for example, proline analogs, cishydroxyproline,d,L-3,4-dehydroproline, Thiaproline, alpha,alpha-dipyridyl,aminopropionitrile fumarate; 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone;Methotrexate; Mitoxantrone; Heparin; Interferons; 2 Macroglobulin-serum;ChIMP-3 (Pavloffet al., J. Bio. Chem. 267:17321-17326, 1992);Chymostatin (Tomkinson et al., Biochem J. 286:475-480, 1992);Cyclodextrin Tetradecasulfate; Eponemycin; Camptothecin; Fumagillin(Ingber et al., Nature 348:555-557, 1990); Gold Sodium Thiomalate(“GST”; Matsubara and Ziff, J. Clin. Invest. 79:1440-1446, 1987);anticollagenase-serum; alpha2-antiplasmin (Holmes et al., J. Biol. Chem.262(4):1659-1664, 1987); Bisantrene (National Cancer Institute);Lobenzarit disodium (N-(2)-carboxyphenyl-4-chloroanthronilic aciddisodium or “CCA”; (Takeuchi et al., Agents Actions 36:312-316, 1992);and metalloproteinase inhibitors such as BB94.

[0548] Additional anti-angiogenic factors that may also be utilizedwithin the context of the present invention include Thalidomide,(Celgene, Warren, N.J.); Angiostatic steroid; AGM-1470 (H. Brem and J.Folkman J Pediatr. Surg. 28:445-51 (1993)); an integrin alpha v beta 3antagonist (C. Storgard et al., J Clin. Invest. 103:47-54 (1999));carboxynaminolmidazole; Carboxyamidotriazole (CAI) (National CancerInstitute, Bethesda, Md.); Conbretastatin A-4 (CA4P) (OXiGENE, Boston,Mass.); Squalamine (Magainin Pharmaceuticals, Plymouth Meeting, Pa.);TNP-470, (Tap Pharmaceuticals, Deerfield, Ill.); ZD-0101 AstraZeneca(London, UK); APRA (CT2584); Benefin, Byrostatin-1 (SC339555); CGP-41251(PKC 412); CM101; Dexrazoxane (ICRF187); DMXAA; Endostatin;Flavopridiol; Genestein; GTE; ImmTher; Iressa (ZD1839); Octreotide(Somatostatin); Panretin; Penacillamine; Photopoint; PI-88; Prinomastat(AG-3340) Purlytin; Suradista (FCE26644); Tamoxifen (Nolvadex);Tazarotene; Tetrathiomolybdate; Xeloda (Capecitabine); and5-Fluorouracil.

[0549] Anti-angiogenic agents that may be administered in combinationwith the compounds of the invention may work through a variety ofmechanisms including, but not limited to, inhibiting proteolysis of theextracellular matrix, blocking the function of endothelialcell-extracellular matrix adhesion molecules, by antagonizing thefunction of angiogenesis inducers such as growth factors, and inhibitingintegrin receptors expressed on proliferating endothelial cells.Examples of anti-angiogenic inhibitors that interfere with extracellularmatrix proteolysis and which may be administered in combination with theantibody and antibody compositions of the invention include, but are notlimited to, AG-3340 (Agouron, La Jolla, Calif.), BAY-12-9566 (Bayer,West Haven, Conn.), BMS-275291 (Bristol Myers Squibb, Princeton, N.J.),CGS-27032A (Novartis, East Hanover, N.J.), Marimastat (British Biotech,Oxford, UK), and Metastat (Aeterna, St-Foy, Quebec). Examples ofanti-angiogenic inhibitors that act by blocking the function ofendothelial cell-extracellular matrix adhesion molecules and which maybe administered in combination with the antibody and antibodycompositions of the invention include, but are not limited to,EMD-121974 (Merck KcgaA Darmstadt, Germany) and Vitaxin (Ixsys, LaJolla, Calif./Medimmune, Gaithersburg, Md.). Examples of anti-angiogenicagents that act by directly antagonizing or inhibiting angiogenesisinducers and which may be administered in combination with the antibodyand antibody compositions of the invention include, but are not limitedto, Angiozyme (Ribozyme, Boulder, Colo.), Anti-VEGF antibody (Genentech,S. San Francisco, Calif.), PTK-787/ZK-225846 (Novartis, Basel,Switzerland), SU-101 (Sugen, S. San Francisco, Calif.), SU-5416 (Sugen/Pharmacia Upjohn, Bridgewater, N.J.), and SU-6668 (Sugen). Otheranti-angiogenic agents act to indirectly inhibit angiogenesis. Examplesof indirect inhibitors of angiogenesis which may be administered incombination with the antibody and antibody compositions of the inventioninclude, but are not limited to, IM-862 (Cytran, Kirkland, Wash.),Interferon-alpha, IL-12 (Roche, Nutley, N.J.), and Pentosan polysulfate(Georgetown University, Washington, D.C.).

[0550] In particular embodiments, the use of antibody and antibodycompositions of the invention in combination with anti-angiogenic agentsis contemplated for the treatment, prevention, and/or amelioration of anautoimmune disease, such as for example, an autoimmune disease describedherein.

[0551] In a particular embodiment, the use of antibody and antibodycompositions of the invention in combination with anti-angiogenic agentsis contemplated for the treatment, prevention, and/or amelioration ofarthritis. In a more particular embodiment, the use of antibody andantibody compositions of the invention in combination withanti-angiogenic agents is contemplated for the treatment, prevention,and/or amelioration of rheumatoid arthritis.

[0552] In another embodiment, antibody and antibody compositions of theinvention are administered in combination with an anticoagulant.Anticoagulants that may be administered with the antibody and antibodycompositions of the invention include, but are not limited to, heparin,warfarin, and aspirin. In a specific embodiment, antibody and antibodycompositions of the invention are administered in combination withheparin and/or warfarin. In another specific embodiment, antibody andantibody compositions of the invention are administered in combinationwith warfarin. In another specific embodiment, antibody and antibodycompositions of the invention are administered in combination withwarfarin and aspirin. In another specific embodiment, antibody andantibody compositions of the invention are administered in combinationwith heparin. In another specific embodiment, antibody and antibodycompositions of the invention are administered in combination withheparin and aspirin.

[0553] In another embodiment, antibody and antibody compositions of theinvention are administered in combination with an agent that suppressesthe production of anticardiolipin antibodies. In specific embodiments,the polynucleotides of the invention are administered in combinationwith an agent that blocks and/or reduces the ability of anticardiolipinantibodies to bind phospholipid-binding plasma protein beta2-glycoprotein I(b2GPI).

[0554] In certain embodiments, antibody and antibody compositions of theinvention are administered in combination with antiretroviral agents,nucleoside reverse transcriptase inhibitors, non-nucleoside reversetranscriptase inhibitors, and/or protease inhibitors. Nucleoside reversetranscriptase inhibitors that may be administered in combination withthe antibody and antibody compositions of the invention, include, butare not limited to, RETROVIR™ (zidovudine/AZT), VIDEX™ (didanosine/ddi),HIVID™ (zalcitabine/ddC), ZERIT™ (stavudine/d4T), EPIVIR™(lamivudine/3TC), and COMBIVIR™ (zidovudine/lamivudine). Non-nucleosidereverse transcriptase inhibitors that may be administered in combinationwith the antibody and antibody compositions of the invention, include,but are not limited to, VIRAMUNE™ (nevirapine), RESCRIPTOR™(delavirdine), and SUSTIVA™ (efavirenz). Protease inhibitors that may beadministered in combination with the antibody and antibody compositionsof the invention, include, but are not limited to, CRIXIVAN™(indinavir), NORVIR™ (ritonavir), INVIRASE™ (saquinavir), and VIRACEPT™(nelfinavir). In a specific embodiment, antiretroviral agents,nucleoside reverse transcriptase inhibitors, non-nucleoside reversetranscriptase inhibitors, and/or protease inhibitors may be used in anycombination with antibody and antibody compositions of the invention totreat, prevent, and/or diagnose AIDS and/or to treat, prevent, and/ordiagnose HIV infection.

[0555] In other embodiments, antibody and antibody compositions of theinvention may be administered in combination with anti-opportunisticinfection agents. Anti-opportunistic agents that may be administered incombination with the antibody and antibody compositions of theinvention, include, but are not limited to,TRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMDINE™, ATOVAQUONE™,ISONIAZID™, RIFAMPIN™, PYRAZINAMIDE™, ETHAMBUTOL™, RIFABUTIN™,CLARITHROMYCIN™, AZITHROMYCIN™, GANCICLOVIR™, FOSCARNET™, CIDOFOVIR™,FLUCONAZOLE™, ITRACONAZOLE™, KETOCONAZOLE™, ACYCLOVIR™, FAMCICOLVIR™,PYRIMETHAMINE™, LEUCOVORIN™, NEUPOGEN™ (filgrastim/G-CSF), and LEUKINE™(sargramostim/GM-CSF). In a specific embodiment, antibody and antibodycompositions of the invention are used in any combination withTRIMETHOPRIM-SULFAMETHOXAZOLE™, DAPSONE™, PENTAMIDINE™, and/orATOVAQUONE™ to prophylactically treat, prevent, and/or diagnose anopportunistic Pneumocystis carinii pneumonia infection. In anotherspecific embodiment, antibody and antibody compositions of the inventionare used in any combination with ISONIAZD™, RIFAMPIN™, PYRAZINAMIDE™,and/or ETHAMBUTOL™ to prophylactically treat, prevent, and/or diagnosean opportunistic Mycobacterium avium complex infection. In anotherspecific embodiment, antibody and antibody compositions of the inventionare used in any combination with RIFABUTIN™, CLARITHROMYCIN™, and/orAZITHROMYCIN™ to prophylactically treat, prevent, and/or diagnose anopportunistic Mycobacterium tuberculosis infection. In another specificembodiment, antibody and antibody compositions of the invention are usedin any combination with GANCICLOVIR™, FOSCARNET™, and/or CIDOFOVIR™ toprophylactically treat, prevent, and/or diagnose an opportunisticcytomegalovirus infection. In another specific embodiment, antibody andantibody compositions of the invention are used in any combination withFLUCONAZOLE™, ITRACONAZOLE™, and/or KETOCONAZOLE™ to prophylacticallytreat, prevent, and/or diagnose an opportunistic fungal infection. Inanother specific embodiment, antibody and antibody compositions of theinvention are used in any combination with ACYCLOVIR™ and/orFAMCICOLVIR™ to prophylactically treat, prevent, and/or diagnose anopportunistic herpes simplex virus type I and/or type II infection. Inanother specific embodiment, antibody and antibody compositions of theinvention are used in any combination with PYRIMETHAMINE™ and/orLEUCOVORIN™ to prophylactically treat, prevent, and/or diagnose anopportunistic Toxoplasma gondii infection. In another specificembodiment, antibody and antibody compositions of the invention are usedin any combination with LEUCOVORIN™ and/or NEUPOGEN™ to prophylacticallytreat, prevent, and/or diagnose an opportunistic bacterial infection.

[0556] In a further embodiment, the antibody and antibody compositionsof the invention are administered in combination with an antiviralagent. Antiviral agents that may be administered with the antibody andantibody compositions of the invention include, but are not limited to,acyclovir, ribavirin, amantadine, and remantidine.

[0557] In a further embodiment, the antibody and antibody compositionsof the invention are administered in combination with an antibioticagent. Antibiotic agents that may be administered with the antibody andantibody compositions of the invention include, but are not limited to,amoxicillin, aminoglycosides, beta-lactam (glycopeptide),beta-lactamases, Clindamycin, chloramphenicol, cephalosporins,ciprofloxacin, ciprofloxacin, erythromycin, fluoroquinolones,macrolides, metronidazole, penicillins, quinolones, rifampin,streptomycin, sulfonamide, tetracyclines, trimethoprim,trimethoprim-sulfamthoxazole, and vancomycin.

[0558] Conventional nonspecific immunosuppressive agents, that may beadministered in combination with the antibody and antibody compositionsof the invention include, but are not limited to, steroids,cyclosporine, cyclosporine analogs cyclophosphamide, cyclophosphamideIV, methylprednisolone, prednisolone, azathioprine, FK-506,15-deoxyspergualin, and other immunosuppressive agents that act bysuppressing the function of responding T cells.

[0559] In specific embodiments, antibody and antibody compositions ofthe invention are administered in combination with immunosuppressants.Immunosuppressants preparations that may be administered with theantibody and antibody compositions of the invention include, but are notlimited to, ORTHOCLONE™ (OKT3), SANDIMMUNE™/NEORAL™/SANGDYA™(cyclosporin), PROGRAF™ (tacrolimus), CELLCEPT™ (mycophenolate),Azathioprine, glucorticosteroids, and RAPAMUNE™ (sirolimus). In aspecific embodiment, immunosuppressants may be used to prevent rejectionof organ or bone marrow transplantation.

[0560] In a preferred embodiment, the antibody and antibody compositionsof the invention are administered in combination with steroid therapy.Steroids that may be administered in combination with the antibody andantibody compositions of the invention, include, but are not limited to,oral corticosteroids, prednisone, and methylprednisolone (e.g., IVmethylprednisolone). In a specific embodiment, antibody and antibodycompositions of the invention are administered in combination withprednisone. In a further specific embodiment, the antibody and antibodycompositions of the invention are administered in combination withprednisone and an immunosuppressive agent. Immunosuppressive agents thatmay be administered with the antibody and antibody compositions of theinvention and prednisone are those described herein, and include, butare not limited to, azathioprine, cylophosphamide, and cyclophosphamideIV. In a another specific embodiment, antibody and antibody compositionsof the invention are administered in combination withmethylprednisolone. In a further specific embodiment, the antibody andantibody compositions of the invention are administered in combinationwith methylprednisolone and an immunosuppressive agent.Immunosuppressive agents that may be administered with the antibody andantibody compositions of the invention and methylprednisolone are thosedescribed herein, and include, but are not limited to, azathioprine,cylophosphamide, and cyclophosphamide IV.

[0561] In a preferred embodiment, the antibody and antibody compositionsof the invention are administered in combination with an antimalarial.Antimalarials that may be administered with the antibody and antibodycompositions of the invention include, but are not limited to,hydroxychloroquine, chloroquine, and/or quinacrine.

[0562] In a preferred embodiment, the antibody and antibody compositionsof the invention are administered in combination with an NSAID.

[0563] In a nonexclusive embodiment, the antibody and antibodycompositions of the invention are administered in combination with one,two, three, four, five, ten, or more of the following drugs: NRD-101(Hoechst Marion Roussel), diclofenac (Dimethaid), oxaprozin potassium(Monsanto), mecasermin (Chiron), T-614 (Toyama), pemetrexed disodium(Eli Lilly), atreleuton (Abbott), valdecoxib (Monsanto), eltenac (BykGulden), campath, AGM-1470 (Takeda), CDP-571 (Celltech Chiroscience),CM-101 (CarboMed), ML-3000 (Merckle), CB-2431 (KS Biomedix), CBF-BS2 (KSBiomedix), IL-1Ra gene therapy (Valentis), JTE-522 (Japan Tobacco),paclitaxel (Angiotech), DW-166HC (Dong Wha), darbufelone mesylate(Warner-Lambert), soluble TNF receptor 1 (synergen; Amgen), IPR-6001(Institute for Pharmaceutical Research), trocade (Hoffman-La Roche),EF-5 (Scotia Pharmaceuticals), BIIL-284 (Boehringer Ingelheim),BIIF-1149 (Boehringer Ingelheim), LeukoVax (Inflammatics), MK-663(Merck), ST-1482 (Sigma-Tau), and butixocort propionate (WarnerLambert).

[0564] In a preferred embodiment, the antibody and antibody compositionsof the invention are administered in combination with one, two, three,four, five or more of the following drugs: methotrexate, sulfasalazine,sodium aurothiomalate, auranofin, cyclosporine, penicillamine,azathioprine, an antimalarial drug (e.g., as described herein),cyclophosphamide, chlorambucil, gold, ENBREL™ (Etanercept), anti-TNFantibody, LJP 394 (La Jolla Pharmaceutical Company, San Diego, Calif.)and prednisolone.

[0565] In a more preferred embodiment, the antibody and antibodycompositions of the invention are administered in combination with anantimalarial, methotrexate, anti-TNF antibody, ENBREL™ and/orsuflasalazine. In one embodiment, the antibody and antibody compositionsof the invention are administered in combination with methotrexate. Inanother embodiment, the antibody and antibody compositions of theinvention are administered in combination with anti-TNF antibody. Inanother embodiment, the antibody and antibody compositions of theinvention are administered in combination with methotrexate and anti-TNFantibody. In another embodiment, the antibody and antibody compositionsof the invention are administered in combination with suflasalazine. Inanother specific embodiment, the antibody and antibody compositions ofthe invention are administered in combination with methotrexate,anti-TNF antibody, and suflasalazine. In another embodiment, theantibody and antibody compositions of the invention are administered incombination ENBREL™. In another embodiment, the antibody and antibodycompositions of the invention are administered in combination withENBREL™ and methotrexate. In another embodiment, the antibody andantibody compositions of the invention are administered in combinationwith ENBREL™, methotrexate and suflasalazine. In another embodiment, theantibody and antibody compositions of the invention are administered incombination with ENBREL™, methotrexate and suflasalazine. In otherembodiments, one or more antimalarials is combined with one of theabove-recited combinations. In a specfic embodiment, the antibody andantibody compositions of the invention are administered in combinationwith an antimalarial (e.g., hydroxychloroquine), ENBREL™, methotrexateand suflasalazine. In another specfic embodiment, the antibody andantibody compositions of the invention are administered in combinationwith an antimalarial (e.g., hydroxychloroquine), sulfasalazine, anti-TNFantibody, and methotrexate.

[0566] In an additional embodiment, antibody and antibody compositionsof the invention are administered alone or in combination with one ormore intravenous immune globulin preparations. Intravenous immuneglobulin preparations that may be administered with the antibody andantibody compositions of the invention include, but not limited to,GAMMAR™, IVEEGAM™, SANDOGLOBULIN™, GAMMAGARD S/D™, and GAMIMUNE™. In aspecific embodiment, antibody and antibody compositions of the inventionare administered in combination with intravenous immune globulinpreparations in transplantation therapy (e.g., bone marrow transplant).

[0567] CD40 ligand (CD40L), a soluble form of CD40L (e.g., AVREND™),biologically active fragments, variants, or derivatives of CD40L,anti-CD40L antibodies (e.g., agonistic or antagonistic antibodies),and/or anti-CD40 antibodies (e.g., agonistic or antagonisticantibodies).

[0568] In an additional embodiment, the antibody and antibodycompositions of the invention are administered alone or in combinationwith an anti-inflammatory agent. Anti-inflammatory agents that may beadministered with the antibody and antibody compositions of theinvention include, but are not limited to, glucocorticoids and thenonsteroidal anti-inflammatories, aminoarylcarboxylic acid derivatives,arylacetic acid derivatives, arylbutyric acid derivatives,arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles,pyrazolones, salicylic acid derivatives, thiazinecarboxamides,e-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyricacid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide,ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein,oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, andtenidap.

[0569] In another embodiment, compostions of the invention areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents that may be administered with the antibody andantibody compositions of the invention include, but are not limited to,antibiotic derivatives (e.g., doxorubicin, bleomycin, daunorubicin, anddactinomycin); antiestrogens (e.g., tamoxifen); antimetabolites (e.g.,fluorouracil, 5-FU, methotrexate, floxuridine, interferon alpha-2b,glutamic acid, plicamycin, mercaptopurine, and 6-thioguanine); cytotoxicagents (e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside,cyclophosphamide, estramustine, hydroxyurea, procarbazine, mitomycin,busulfan, cis-platin, and vincristine sulfate); hormones (e.g.,medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol,estradiol, megestrol acetate, methyltestosterone, diethylstilbestroldiphosphate, chlorotrianisene, and testolactone); nitrogen mustardderivatives (e.g., mephalen, chorambucil, mechlorethamine (nitrogenmustard) and thiotepa); steroids and combinations (e.g., bethamethasonesodium phosphate); and others (e.g., dicarbazine, asparaginase,mitotane, vincristine sulfate, vinblastine sulfate, and etoposide).

[0570] In a specific embodiment, antibody and antibody compositions ofthe invention are administered in combination with CHOP(cyclophosphamide, doxorubicin, vincristine, and prednisone) or anycombination of the components of CHOP. In another embodiment, antibodyand antibody compositions of the invention are administered incombination with Rituximab. In a further embodiment, antibody andantibody compositions of the invention are administered with Rituxmaband CHOP, or Rituxmab and any combination of the components of CHOP.

[0571] In an additional embodiment, the antibody and antibodycompositions of the invention are administered in combination withcytokines. Cytokines that may be administered with the antibody andantibody compositions of the invention include, but are not limited to,GM-CSF, G-CSF, IL2, IL3, IL4, IL5, IL6, IL7, IL10, IL12, IL13, IL15,anti-CD40, CD40L, IFN-alpha, IFN-beta, IFN-gamma, TNF-alpha, andTNF-beta. In preferred embodiments, antibody and antibody compositionsof the invention are administered with BLyS (e.g., amino acids 134-285of SEQ IF D NO:3228). In another embodiment, antibody and antibodycompositions of the invention may be administered with any interleukin,including, but not limited to, IL-1alpha, IL-1beta, IL-2, IL-3, IL-4,IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15,IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, and IL-22. In preferredembodiments, the antibody and antibody compositions of the invention areadministered in combination with IL4 and IL10.

[0572] In one embodiment, the antibody and antibody compositions of theinvention are administered in combination with one or more chemokines.In specific embodiments, the antibody and antibody compositions of theinvention are administered in combination with an α(C×C) chemokineselected from the group consisting of gamma-interferon inducibleprotein-10 (γIP-10), interleukin-8 (IL-8), platelet factor-4 (PF4),neutrophil activating protein (NAP-2), GRO-α, GRO-β, GRO-γ,neutrophil-activating peptide (ENA-78), granulocyte chemoattractantprotein-2 (GCP-2), and stromal cell-derived factor-1 (SDF-1, or pre-Bcell stimulatory factor (PB SF)); and/or a β(CC) chemokine selected fromthe group consisting of: RANTES (regulated on activation, normal Texpressed and secreted), macrophage inflammatory protein-1 alpha(MIP-1α), macrophage inflammatory protein-1 beta (MIP-1β), monocytechemotactic protein-1 (MCP-1), monocyte chemotactic protein-2 (MCP-2),monocyte chemotactic protein-3 (MCP-3), monocyte chemotactic protein-4(MCP-4) macrophage inflammatory protein-1 gamma (MIP-1γ), macrophageinflammatory protein-3 alpha (MIP-3α), macrophage inflammatory protein-3beta (MIP-3β), macrophage inflammatory protein-4 (MIP-4/DC-CK-1/PARC),eotaxin, Exodus, and I-309; and/or the γ(C) chemokine, lymphotactin.

[0573] In another embodiment, the antibody and antibody compositions ofthe invention are administered with chemokine beta-8, chemokine beta-1,and/or macrophage inflammatory protein-4. In a preferred embodiment, theantibody and antibody compositions of the invention are administeredwith chemokine beta-8.

[0574] In an additional embodiment, the antibody and antibodycompositions of the invention are administered in combination with anIL-4 antagonist. IL-4 antagonists that may be administered with theantibody and antibody compositions of the invention include, but are notlimited to: soluble IL-4 receptor polypeptides, multimeric forms ofsoluble IL-4 receptor polypeptides; anti-IL-4 receptor antibodies thatbind the IL-4 receptor without transducing the biological signalelicited by IL-4, anti-IL4 antibodies that block binding of IL-4 to oneor more IL-4 receptors, and muteins of IL-4 that bind IL-4 receptors butdo not transduce the biological signal elicited by IL-4. Preferably, theantibodies employed according to this method are monoclonal antibodies(including antibody fragments, such as, for example, those describedherein).

[0575] The invention also encompasses combining the polynucleotidesand/or polypeptides of the invention (and/or agonists or antagoniststhereof) with other proposed or conventional hematopoietic therapies.Thus, for example, the polynucleotides and/or polypeptides of theinvention (and/or agonists or antagonists thereof) can be combined withcompounds that singly exhibit erythropoietic stimulatory effects, suchas erythropoietin, testosterone, progenitor cell stimulators,insulin-like growth factor, prostaglandins, serotonin, cyclic AMP,prolactin, and triiodothyzonine. Also encompassed are combinations ofthe antibody and antibody compositions of the invention with compoundsgenerally used to treat aplastic anemia, such as, for example,methenolene, stanozolol, and nandrolone; to treat iron-deficiencyanemia, such as, for example, iron preparations; to treat malignantanemia, such as, for example, vitamin B₁₂ and/or folic acid; and totreat hemolytic anemia, such as, for example, adrenocortical steroids,e.g., corticoids. See e.g., Resegotti et al., Panminerva Medica,23:243-248 (1981); Kurtz, FEBS Letters, 14a:105-108 (1982); McGonigle etal., Kidney Int., 25:437-444 (1984); and Pavlovic-Kantera, Expt.Hematol., 8(supp. 8) 283-291 (1980), the contents of each of which arehereby incorporated by reference in their entireties.

[0576] Compounds that enhance the effects of or synergize witherythropoietin are also useful as adjuvants herein, and include but arenot limited to, adrenergic agonists, thyroid hormones, androgens,hepatic erythropoietic factors, erythrotropins, and erythrogenins, Seefor e.g., Dunn, “Current Concepts in Erythropoiesis”, John Wiley andSons (Chichester, England, 1983); Kalmani, Kidney Int., 22:383-391(1982); Shahidi, New Eng. J. Med., 289:72-80 (1973); Urabe et al., J.Exp. Med., 149:1314-1325 (1979); Billat et al., Expt. Hematol.,10:133-140 (1982); Naughton et al., Acta Haemat, 69:171-179 (1983);Cognote et al. in abstract 364, Proceedings 7th Intl. Cong. ofEndocrinology (Quebec City, Quebec, Jul. 1-7, 1984); and Rothman et al.,1982, J. Surg. Oncol., 20:105-108 (1982). Methods for stimulatinghematopoiesis comprise administering a hematopoietically effectiveamount (i.e., an amount which effects the formation of blood cells) of apharmaceutical composition containing polynucleotides and/orpoylpeptides of the invention (and/or agonists or antagonists thereof)to a patient. The polynucleotides and/or polypeptides of the inventionand/or agonists or antagonists thereof is administered to the patient byany suitable technique, including but not limited to, parenteral,sublingual, topical, intrapulmonary and intranasal, and those techniquesfurther discussed herein. The pharmaceutical composition optionallycontains one or more members of the group consisting of erythropoietin,testosterone, progenitor cell stimulators, insulin-like growth factor,prostaglandins, serotonin, cyclic AMP, prolactin, triiodothyzonine,methenolene, stanozolol, and nandrolone, iron preparations, vitamin B₁₂,folic acid and/or adrenocortical steroids.

[0577] In an additional embodiment, the antibody and antibodycompositions of the invention are administered in combination withhematopoietic growth factors. Hematopoietic growth factors that may beadministered with the antibody and antibody compositions of theinvention include, but are not limited to, LEUKINE™ (SARGRAMOSTIM™) andNEUPOGEN™ (FILGRASTIM™).

[0578] In an additional embodiment, the antibody and antibodycompositions of the invention are administered in combination withfibroblast growth factors. Fibroblast growth factors that may beadministered with the antibody and antibody compositions of theinvention include, but are not limited to, FGF-1, FGF-2, FGF-3, FGF-4,FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13,FGF-14, and FGF-15.

[0579] Additionally, the antibody and antibody compositions of theinvention may be administered alone or in combination with othertherapeutic regimens, including but not limited to, radiation therapy.Such combinatorial therapy may be administered sequentially and/orconcomitantly.

[0580] Kits

[0581] The invention also provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration.

[0582] The present invention provides kits that can be used in the abovemethods. In one embodiment, a kit comprises an antibody of theinvention, preferably a purified antibody, in one or more containers. Inan alternative embodiment, a kit comprises an antibody fragment thatimmunospecifically binds to BLyS. In a specific embodiment, the kits ofthe present invention contain a substantially isolated BLyS polypeptideas a control. Preferably, the kits of the present invention furthercomprise a control antibody which does not react with BLyS. In anotherspecific embodiment, the kits of the present invention contain a meansfor detecting the binding of an antibody to BLyS (e.g., the antibody maybe conjugated to a detectable substrate such as a fluorescent compound,an enzymatic substrate, a radioactive compound or a luminescentcompound, or a second antibody which recognizes the first antibody maybe conjugated to a detectable substrate). In specific embodiments, thekit may include a recombinantly produced or chemically synthesized BLyS.The BLyS provided in the kit may also be attached to a solid support. Ina more specific embodiment the detecting means of the above-describedkit includes a solid support to which BLyS is attached. Such a kit mayalso include a non-attached reporter-labeled anti-human antibody. Inthis embodiment, binding of the antibody to BLyS can be detected bybinding of the said reporter-labeled antibody.

[0583] In an additional embodiment, the invention includes a diagnostickit for use in screening serum containing antigens of the polypeptide ofthe invention. The diagnostic kit includes a substantially isolatedantibody specifically immunoreactive with BLyS, and means for detectingthe binding of BLyS to the antibody. In one embodiment, the antibody isattached to a solid support. In a specific embodiment, the antibody maybe a monoclonal antibody. The detecting means of the kit may include asecond, labeled monoclonal antibody. Alternatively, or in addition, thedetecting means may include a labeled, competing antigen.

[0584] In one diagnostic configuration, test serum is reacted with asolid phase reagent having a surface-bound BLyS obtained by the methodsof the present invention. After BLyS binds to a specific antibody, theunbound serum components are removed by washing, reporter-labeledanti-human antibody is added, unbound anti-human antibody is removed bywashing, and a reagent is reacted with reporter-labeled anti-humanantibody to bind reporter to the reagent in proportion to the amount ofbound anti-BLyS antibody on the solid support. Typically, the reporteris an enzyme which is detected by incubating the solid phase in thepresence of a suitable fluorometric, luminescent or colorimetricsubstrate.

[0585] The solid surface reagent in the above assay is prepared by knowntechniques for attaching protein material to solid support material,such as polymeric beads, dip sticks, 96-well plate or filter material.These attachment methods generally include non-specific adsorption ofthe protein to the support or covalent attachment of the protein,typically through a free amine group, to a chemically reactive group onthe solid support, such as an activated carboxyl, hydroxyl, or aldehydegroup. Alternatively, streptavidin coated plates can be used inconjunction with biotinylated antigen(s).

[0586] Thus, the invention provides an assay system or kit for carryingout this diagnostic method. The kit generally includes a support withsurface-bound recombinant BLyS, and a reporter-labeled anti-humanantibody for detecting surface-bound anti-BLyS antibody.

[0587] In specific embodiments, the present invention encompasses asingle chain Fv (scFv) having an amino acid sequence of one of SEQ IDNOS: 1 to 2128.

[0588] In specific embodiments, the present invention encompasses asingle chain Fv (scFv) having an amino acid sequence of one of SEQ IDNOS: 1 to 46, 321 to 329, 1563 to 1595, and 1881 to 1908.

[0589] In specific embodiments, the present invention encompasses asingle chain Fv (scFv) having an amino acid sequence of one of SEQ IDNOS: 1563 to 1880.

[0590] In specific embodiments, the present invention encompasses asingle chain Fv (scFv) having an amino acid sequence of one of SEQ IDNOS: 1881 to 2128.

[0591] In specific embodiments, the present invention encompasses asingle chain Fv (scfv) having an amino acid sequence of one of SEQ IDNOS: 1 to 1562.

[0592] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VH domain from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1 to 2128, wherein saidantibody or fragment thereof immunospecifically binds BLyS.

[0593] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VH domain from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1 to 46, 321 to 329, 1563to 1595, and 1881 to 1908.

[0594] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VH domain from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1881 to 2128, and in whichsaid antibody or fragment thereof immunospecifically binds to themembrane-bound form of BLyS.

[0595] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VH domain from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1563 to 1880, and in whichsaid antibody or fragment thereof immunospecifically binds to thesoluble form of BLyS.

[0596] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VL domain from an scfv havingan amino acid sequence of one of SEQ ID NOS: 1 to 2128, wherein saidantibody or fragment thereof immunospecifically binds BLyS.

[0597] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VL domain from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1 to 46, 321 to 329, 1563to 1595, and 1881 to 1908.

[0598] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VL domain from an scfv havingan amino acid sequence of one of SEQ ID NOS: 1881 to 2128, and in whichsaid antibody or fragment thereof immunospecifically binds to themembrane-bound form of BLyS.

[0599] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VL domain from an scfv havingan amino acid sequence of one of SEQ ID NOS: 1563 to 1880, and in whichsaid antibody or fragment thereof immunospecifically binds to thesoluble form of BLyS.

[0600] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VL domain from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1 to 2128, wherein saidantibody or fragment thereof immunospecifically binds BLyS and whichalso comprises a VH domain from an scFv having an amino acid sequence ofone of SEQ ID NOS: 1 to 2128.

[0601] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising a VL domain from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1 to 2128, wherein saidantibody or fragment thereof immunospecifically binds BLyS and whichalso comprises a VH domain from an scFv having an amino acid sequence ofone of SEQ ID NOS: 1 to 2128 and in which said VL and said VH domainsare derived from the same scFv having an amino acid sequence of one ofSEQ ID NOS: 1 to 2128.

[0602] In specific embodiments, the present invention encompasses anantibody or fragment thereof comprising an amino acid sequence of one ofSEQ ID NOS: 2129 to 3227 wherein said antibody or fragment thereofimmunospecifically binds BLyS.

[0603] In specific embodiments, the antibody or fragment thereof of theinvention is a whole immunoglobulin molecule.

[0604] In specific embodiments, the antibody or fragment thereof of theinvention is a Fab fragment.

[0605] In specific embodiments, the antibody or fragment thereof of theinvention is a Fv fragment.

[0606] In specific embodiments, the present invention encompasses achimeric protein comprising the antibody or fragment thereof of theinvention covalently linked to a heterologous polypeptide.

[0607] In specific embodiments, the present invention encompasses acomposition comprising two or more types of antibodies or fragments orvariants thereof, each of which type immunospecifically binds to BLyS,and each of which type of antibody or fragment thereof comprises a VHdomain from a different scFv having an amino acid sequence of one of SEQID NOS: 1 to 2128.

[0608] In specific embodiments, the present invention encompasses acomposition comprising two or more types of antibodies or fragments orvariants thereof, each of which type immunospecifically binds to BLyS,and each of which type of antibody or fragment thereof comprises a VLdomain from a different scFv having an amino acid sequence of one of SEQID NOS: 1 to 2128.

[0609] In specific embodiments, the present invention encompasses acomposition comprising two or more types of antibodies or fragments orvariants thereof each of which type immunospecifically binds to BLyS,and each of which type of antibody or fragment thereof comprises a VLdomain from a different scFv having an amino acid sequence of one of SEQID NOS: 1 to 2128 and wherein each type of antibody or fragment thereoffurther comprises a VH domain from a different scFv having an amino acidsequence of one of SEQ ID NOS: 1 to 2128.

[0610] In specific embodiments, the present invention encompasses acomposition comprising two or more types of antibodies or fragments orvariants thereof, each of which type immunospecifically binds to BLyS,and each of which type of antibody or fragment thereof comprises a VHCDR3 having an amino acid sequence of one of SEQ ID NOS: 3129 to 3227.

[0611] In specific embodiments, the present invention encompasses apanel of two or more types of antibodies or fragments or variantsthereof, each of which type immunospecifically binds to BLyS, and eachof which type of antibody or fragment thereof comprises a VH domain froma different scFv having an amino acid sequence of one of SEQ ID NO: 1 to2128.

[0612] In specific embodiments, the present invention encompasses apanel of two or more types of antibodies or fragments or variantsthereof, each of which type immunospecifically binds to BLyS, and eachof which type of antibody or fragment thereof comprises a VL domain froma different scFv having an amino acid sequence of one of SEQ ID NO: 1 to2128.

[0613] In specific embodiments, the present invention encompasses apanel of two or more types of antibodies or fragments or variantsthereof, each of which type immunospecifically binds to BLyS, and eachof which type of antibody or fragment thereof comprises a VL domain froma different scFv having an amino acid sequence of one of SEQ ID NO: 1 to2128 and wherein each type of antibody or fragment further comprises aVH domain from a different scFv having an amino acid sequence of one ofSEQ ID NOS: 1 to 2128.

[0614] In specific embodiments, the present invention encompasses apanel of two or more antibodies or fragments or variants thereof, eachof which type immunospecifically binds to BLyS, and each of which typeof antibody or fragment thereof comprises a VHCDR3 from a different scFvhaving an amino acid sequence of one of SEQ ID NOS: 2129 to 3227.

[0615] In specific embodiments, the antibodies or fragments thereof ofthe antibody panel of the invention, are each in a well of a 96 wellplate.

[0616] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VH domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 2128, whereinsaid antibody or fragment thereof immunospecifically binds BLyS.

[0617] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VH domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 46, 321 to 329,1563 to 1595, and 1881 to 1908, wherein said antibody or fragmentthereof immunospecifically binds BLyS.

[0618] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VH domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1881 to 1908,wherein the antibody of fragment thereof immunospecifically binds themembrane-bound form of BLyS.

[0619] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VH domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1563 to 1569,wherein said antibody of fragment thereof immunospecifically binds thesoluble form of BLyS. The present invention also encompasses vectorscomprising the isolated nucleic acid molecule described above, includingvectors comprising a nucleotide sequence which regulates the expressionof the antibody or fragment thereof encoded by the above-describednucleic acid molecule. Additionally the present invention alsoencompasses host cells, including mammalian host cells, comprising theabove-described nucleic acid molecule which is operably linked to aheterologous promoter, as well as host cells, including mammalian hostcells, comprising the above-described vectors. Additionally, the presentinvention also provides a method for producing an antibody or fragmentthereof comprising culturing the above-described host cells underconditions in which the nucleic acid molecule is expressed.

[0620] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VL domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 2128, whereinsaid antibody or fragment thereof immunospecifically binds BLyS. Thepresent invention also encompasses vectors comprising the isolatednucleic acid molecule described above, including vectors comprising anucleotide sequence which regulates the expression of the antibody orfragment thereof encoded by the above-described nucleic acid molecule.Additionally the present invention also encompasses host cells,including mammalian host cells, comprising the above-described nucleicacid molecule which is operably linked to a heterologous promoter, aswell as host cells, including mammalian host cells, comprising theabove-described vectors. Additionally, the present invention alsoprovides a method for producing an antibody or fragment thereofcomprising culturing the above-described host cells under conditions inwhich the nucleic acid molecule is expressed.

[0621] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VL domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 46, 321 to 329,1563 to 1595, and 1881 to 1908, wherein said antibody or fragmentthereof immunospecifically binds BLyS. The present invention alsoencompasses vectors comprising the isolated nucleic acid moleculedescribed above, including vectors comprising a nucleotide sequencewhich regulates the expression of the antibody or fragment thereofencoded by the above-described nucleic acid molecule. Additionally thepresent invention also encompasses host cells, including mammalian hostcells, comprising the above-described nucleic acid molecule which isoperably linked to a heterologous promoter, as well as host cells,including mammalian host cells, comprising the above-described vectors.Additionally, the present invention also provides a method for producingan antibody or fragment thereof comprising culturing the above-describedhost cells under conditions in which the nucleic acid molecule isexpressed.

[0622] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VL domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1881 to 2128,wherein the antibody of fragment thereof immunospecifically binds themembrane-bound form of BLyS. The present invention also encompassesvectors comprising the isolated nucleic acid molecule described above,including vectors comprising a nucleotide sequence which regulates theexpression of the antibody or fragment thereof encoded by theabove-described nucleic acid molecule. Additionally the presentinvention also encompasses host cells, including mammalian host cells,comprising the above-described nucleic acid molecule which is operablylinked to a heterologous promoter, as well as host cells, includingmammalian host cells, comprising the above-described vectors.Additionally, the present invention also provides a method for producingan antibody or fragment thereof comprising culturing the above-describedhost cells under conditions in which the nucleic acid molecule isexpressed.

[0623] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VL domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1563 to 1880,wherein said antibody of fragment thereof immunospecifically binds thesoluble form of BLyS. The present invention also encompasses vectorscomprising the isolated nucleic acid molecule described above, includingvectors comprising a nucleotide sequence which regulates the expressionof the antibody or fragment thereof encoded by the above-describednucleic acid molecule. Additionally the present invention alsoencompasses host cells, including mammalian host cells, comprising theabove-described nucleic acid molecule which is operably linked to aheterologous promoter, as well as host cells, including mammalian hostcells, comprising the above-described vectors. Additionally, the presentinvention also provides a method for producing an antibody or fragmentthereof comprising culturing the above-described host cells underconditions in which the nucleic acid molecule is expressed.

[0624] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VL domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 2128, whereinsaid antibody or fragment thereof immunospecifically binds BLyS andwhich also comprises a VH domain from an scFv having an amino acidsequence of one of SEQ ID NOS: 1 to 2128. The present invention alsoencompasses vectors comprising the isolated nucleic acid moleculedescribed above, including vectors comprising a nucleotide sequencewhich regulates the expression of the antibody or fragment thereofencoded by the above-described nucleic acid molecule. Additionally thepresent invention also encompasses host cells, including mammalian hostcells, comprising the above-described nucleic acid molecule which isoperably linked to a heterologous promoter, as well as host cells,including mammalian host cells, comprising the above-described vectors.Additionally, the present invention also provides a method for producingan antibody or fragment thereof comprising culturing the above-describedhost cells under conditions in which the nucleic acid molecule isexpressed.

[0625] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VL domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 2128, whereinsaid antibody or fragment thereof immunospecifically binds BLyS andwhich also comprises a VH domain from an scFv having an amino acidsequence of one of SEQ ID NOS: 1 to 2128 and in which said VL domain andsaid VH domain are derived from the same scFv having an amino acidsequence of one of SEQ ID NOS: 1 to 2128. The present invention alsoencompasses vectors comprising the isolated nucleic acid moleculedescribed above, including vectors comprising a nucleotide sequencewhich regulates the expression of the antibody or fragment thereofencoded by the above-described nucleic acid molecule. Additionally thepresent invention also encompasses host cells, including mammalian hostcells, comprising the above-described nucleic acid molecule which isoperably linked to a heterologous promoter, as well as host cells,including mammalian host cells, comprising the above-described vectors.Additionally, the present invention also provides a method for producingan antibody or fragment thereof comprising culturing the above-describedhost cells under conditions in which the nucleic acid molecule isexpressed.

[0626] In specific embodiments, the present invention encompasses anisolated nucleic acid molecule comprising a nucleotide sequence encodingan antibody or fragment thereof comprising a VHCDR3 from an scFv havingan amino acid sequence of one of SEQ ID NOS: 2129 to 3227, wherein saidantibody or fragment thereof immunospecifically binds BLyS. The presentinvention also encompasses vectors comprising the isolated nucleic acidmolecule described above, including vectors comprising a nucleotidesequence which regulates the expression of the antibody or fragmentthereof encoded by the above-described nucleic acid molecule.Additionally the present invention also encompasses host cells,including mammalian host cells, comprising the above-described nucleicacid molecule which is operably linked to a heterologous promoter, aswell as host cells, including mammalian host cells, comprising theabove-described vectors. Additionally, the present invention alsoprovides a method for producing an antibody or fragment thereofcomprising culturing the above-described host cells under conditions inwhich the nucleic acid molecule is expressed.

[0627] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a VHdomain encoded by a nucleotide sequence that hybridizes under stringentconditions to a nucleotide sequence encoding a VH domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 2128.

[0628] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a VLdomain encoded by a nucleotide sequence that hybridizes under stringentconditions to a nucleotide sequence encoding a VL domain from an scFvhaving an amino acid sequence of one of SEQ ID NOS: 1 to 2128.

[0629] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a VHdomain encoded by a nucleotide sequence that hybridizes under highlystringent conditions to a nucleotide sequence encoding a VH domain froman scFv having an amino acid sequence of one of SEQ ID NOS: 1 to 2128.

[0630] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a VLdomain encoded by a nucleotide sequence that hybridizes under highlystringent conditions to a nucleotide sequence encoding a VL domain froman scFv having an amino acid sequence of one of SEQ ID NOS: 1 to 2128.

[0631] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a CDRencoded by a nucleotide sequence that hybridizes under stringentconditions to a nucleotide sequence encoding a CDR from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1 to 2128.

[0632] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a CDRencoded by a nucleotide sequence that hybridizes under highly stringentconditions to a nucleotide sequence encoding a CDR from an scFv havingan amino acid sequence of one of SEQ ID NOS: 1 to 2128.

[0633] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a VHCDR3 encoded by a nucleotide sequence that hybridizes under stringentconditions to a nucleotide sequence encoding a VH CDR3 having an aminoacid sequence of one of SEQ ID NOS: 2129 to 3227.

[0634] In specific embodiments, the present invention provides anantibody or fragment thereof that immunospecifically binds to BLyS, saidantibody or fragment thereof comprising an amino acid sequence of a VHCDR3 encoded by a nucleotide sequence that hybridizes under highlystringent conditions to a nucleotide sequence encoding a VH CDR3 havingan amino acid sequence of one of SEQ ID NOS: 2129 to 3227.

[0635] In specific embodiments, the present invention provides a methodfor detecting of aberrant expression of BLyS, comprising:

[0636] assaying the level of BLyS expression in cells or a tissue sampleof an individual using one or more antibodies or fragments or variantsthereof that immunospecifically bind BLyS; and

[0637] comparing the level of BLyS assayed in the cells or a tissuesample with a standard level of BLyS or a level of BLyS in cells or atissue sample from an individual without aberrant BLyS expression,wherein an increase or decrease in the assayed level of BLyS or level incells or a tissue sample from an individual without aberrant BLySexpression compared to the standard level of BLyS is indicative ofaberrant expression.

[0638] In specific embodiments, the present invention provides a methodfor diagnosing a disease or disorder associated with aberrant BLySexpression or activity, comprising:

[0639] administering to a subject an effective amount of a labeledantibody or fragment thereof that immunospecifically binds to BLyS;

[0640] waiting for a time interval following the administering forpermitting the labeled antibody or fragment thereof to preferentiallyconcentrate at sites in the subject where BLyS is expressed;

[0641] determining background level; and

[0642] detecting the labeled antibody or fragment thereof in thesubject, such that detection of labeled antibody or fragment thereofabove the background level indicates that the subject has a particulardisease or disorder associated with aberrant expression of BLyS.

[0643] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above comprises a VHdomain from an scFv having an amino acid sequence of one of SEQ ID NOS:1 to 2128.

[0644] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above comprises a VLdomain from an scFv having an amino acid sequence of one of SEQ ID NOS:1 to 2128.

[0645] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above comprises a VHCDR3 having an amino acid sequence of one of SEQ ID NOS: 2129 to 3227.

[0646] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above is conjugated toa diagnostic agent.

[0647] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above is conjugated toa diagnostic agent wherein the diagnostic agent is horseradishperoxidase, alkaline phosphatase, beta-galactosidase, oracetylcholinesterase.

[0648] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above is conjugated toa diagnostic agent wherein the diagnostic agent is fluorescein,fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride or phycoerythrin.

[0649] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above is conjugated toa diagnostic agent wherein the diagnostic agent is ¹²⁵I, ¹³¹I, ¹¹¹In,⁹⁰Y or ⁹⁹Tc.

[0650] In specific embodiments, the antibody or fragment thereofutilized in the two methods described immediately above is conjugated toa diagnostic agent wherein the diagnostic agent is luciferase, luciferinor aequorin.

[0651] A pharmaceutical composition comprising at least one antibody orfragment thereof of comprising a VH domain from an scFv having an aminoacid sequence of one of SEQ ID NOS: 1 to 2128, wherein said antibody orfragment thereof immunospecifically binds BLyS and a pharmaceuticallyacceptable carrier.

[0652] A pharmaceutical composition comprising at least one antibody orfragment thereof of comprising a VL domain from an scFv having an aminoacid sequence of one of SEQ ID NOS: 1 to 2128, wherein said antibody orfragment thereof immunospecifically binds BLyS and a pharmaceuticallyacceptable carrier.

[0653] A pharmaceutical composition comprising at least one antibody orfragment thereof of comprising a VL domain from an scFv having an aminoacid sequence of one of SEQ ID NOS: 1 to 2128, wherein said antibody orfragment thereof immunospecifically binds BLyS and which also comprisesa VH domain from an scFv having an amino acid sequence of one of SEQ IDNOS: 1 to 2128 and a pharmaceutically acceptable carrier.

[0654] A pharmaceutical composition comprising at least one antibody orfragment thereof of comprising an amino acid sequence of one of SEQ IDNOS: 2129 to 3227 wherein said antibody or fragment thereofimmunospecifically binds BLyS and a pharmaceutically acceptable carrier.

[0655] A method of treating, preventing or ameliorating a disease ordisorder associated with aberrant BLyS expression or activity,comprising administering to an animal in need thereof the pharmaceuticalcomposition comprising at least one antibody or fragment thereof ofcomprising a VL domain from an scFv having an amino acid sequence of oneof SEQ ID NOS: 1 to 2128, wherein said antibody or fragment thereofimmunospecifically binds BLyS and which also comprises a VH domain froman scFv having an amino acid sequence of one of SEQ ID NOS: 1 to 2128and a pharmaceutically acceptable carrier in an amount effective totreat, prevent or ameliorate the disease or disorder. This method may beused to treat an infectious disorder, cancer, and/or an autoimmunedisease such as lupus or glomerular nephritis.

[0656] A method of treating, preventing or ameliorating a disease ordisorder associated with aberrant BLyS expression or activity,comprising administering to an animal in need thereof the pharmaceuticalcomposition comprising at least one antibody or fragment thereof ofcomprising a VL domain from an scFv having an amino acid sequence of oneof SEQ ID NOS: 1 to 2128, wherein said antibody or fragment thereofimmunospecifically binds BLyS and a pharmaceutically acceptable carrierin an amount effective to treat, prevent or ameliorate the disease ordisorder. This method may be used to treat an infectious disorder,cancer, and/or an autoimmune disease such as lupus or glomerularnephritis.

[0657] A method of treating, preventing or ameliorating a disease ordisorder associated with aberrant BLyS expression or activity,comprising administering to an animal in need thereof the pharmaceuticalcomposition comprising at least one antibody or fragment thereof ofcomprising a VL domain from an scFv having an amino acid sequence of oneof SEQ ID NOS: 1 to 2128, wherein said antibody or fragment thereofimmunospecifically binds BLyS and which also comprises a VH domain froman scFv having an amino acid sequence of one of SEQ ID NOS: 1 to 2128and a pharmaceutically acceptable carrier in an amount effective totreat, prevent or ameliorate the disease or disorder. This method may beused to treat an infectious disorder, cancer, and/or an autoimmunedisease such as lupus or glomerular nephritis.

[0658] A method of treating, preventing or ameliorating a disease ordisorder associated with aberrant BLyS expression or activity,comprising administering to an animal in need thereof the pharmaceuticalcomposition of comprising at least one antibody or fragment thereof ofcomprising an amino acid sequence of one of SEQ ID NOS: 2129 to 3227wherein said antibody or fragment thereof immunospecifically binds BLySand a pharmaceutically acceptable carrier in an amount effective totreat, prevent or ameliorate the disease or disorder. This method may beused to treat an infectious disorder, cancer, and/or an autoimmunedisease such as lupus or glomerular nephritis.

[0659] This method may be used to treat an infectious disorder, cancer,and/or an autoimmune disease such as lupus or glomerular nephritis.

EXAMPLES

[0660] Abbreviations

[0661] 0.2 M Tris-HCl, 0.5 mM EDTA, 0.5 M sucrose (TES)

[0662] 1-ethyl-3-[3-dimethylaminopropyl]carbo diimide hydrochloride(EDC)

[0663] 2TY supplemented with 100 μg/ml ampicillin and 2% glucose (2TYAG)

[0664] 2TY supplemented with 100 μg/ml ampicillin and 50 μg/ml kanamycin(2TYAK)

[0665] 3,3′,5,5′-Tetramethyl Benzidine (TMB)

[0666] 50% inhibitory concentration (IC₅₀)

[0667] 6×PBS containing 18% Marvel blocking solution (6×MPBS)

[0668] Absorbance (A)

[0669] Bovine serum albumin (BSA)

[0670] Enzyme linked immunosorbent assay (ELISA)

[0671] Foetal calf serum (FCS)

[0672] Heavy chain variable (V_(H))

[0673] Hepes buffered saline (HBS)

[0674] Horseradish peroxidase (HRP)

[0675] Immobilised Metal Affinity Chromatography (IMAC)

[0676] Isopropyl β-D-thiogalactopyranoside (IPTG)

[0677] Light chain variable (V_(L))

[0678] Multiplicity of infection (MOI)

[0679] N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid] (Hepes)

[0680] Nanomolar (nM)

[0681] N-Hydroxysuccinimide (NHS)

[0682] PBS containing 3% Marvel (MPBS)

[0683] Phosphate Buffered Saline (PBS)

[0684] Phosphate Buffered Saline+0.1% (v/v) Tween 20 (PBST)

[0685] Picomolar (pM)

[0686] Single chain fragment variable (scFv)

[0687] Tumour Necrosis Factor-alpha (TNF-α)

[0688] Tumour Necrosis Factor-beta (TNF-β)

[0689] TNF-related apoptosis inducing ligand (TRAIL)

[0690] Definitions:

[0691] In the following section “immobilized BLyS” refers to a solubleform of BLyS or biotinylated BLyS coated on a plastic assay plate (e.g.,a 96 well plate), but does not refer to histidine tagged BLyS coated ona plastic assay plate; “biotinylated BLyS” is a soluble form of BLySexcept when used to coat an ELISA plate, in which case it would be“immobilized BLyS.” Membrane bound forms of BLyS include, but are notlimited to, U937 and P388 plasma membranes.

Example 1

[0692] Antibodies Immunospecifically Binding to Soluble AndMembrane-Bound BLyS

[0693] A library of phage was screened in an assay to identify thosephage displaying scFvs that immunospecifically bind to the soluble andmembrane-bound forms of BLyS. Phage displaying scFvs that bound toimmobilized BLyS were identified after panning on immobilized BLyS andassessment by ELISA for binding to immobilized BLyS. The BLyS that wasimmobilized on plates for these assays was purified from supernatants ofSf9 cells infected with a baculovirus expression construct as describedin Moore et al., Science 285:260-263 which is hereby incorporated byreference in its entirety. Each of the identified scFvs were thensequenced. Certain sequences were isolated multiple times, thus a panel(panel 1) containing one member of each unique sequences was generatedand further characterized for their ability to immunospecifically bindto the soluble and membrane-bound forms of BLyS.

[0694] The derived amino acid sequences of these scFvs are shown inTable 1 above. The individual V_(H) and V_(L) segments of the scFvs werealigned to the known human germline sequences in V-BASE (Tomlinson etal, www.mrc-cpe.cam.ac.uk) and the closest germline identified.

Example 2

[0695] Specificity of scFvs for BLyS and Membrane-Bound BLyS

[0696] The specificity of each of the scFvs for both BLyS andmembrane-bound BLyS was determined by phage ELISA. BLyS was immobilisedonto plastic as a purified soluble form of the protein or as amembrane-bound form present on plasma membrane preparations from thehuman macrophage-like cell line, U937.

[0697] Maintenance of U937 Cells

[0698] U937 cells are a human monocyte-like, histiocytic lymphoma cellline known to express BLyS on their plasma membranes. They weremaintained in RPMI-1640 supplemented with 4 mM L-glutamine, 10% FCS, 10U penicillin, 100 g/ml streptomycin (all reagents from Sigma). The cellswere thawed from frozen stock and are either used for plasma membranepreparation, or split 1:5, after 2 days in culture when the cell densityreaches 1×10⁶/ml.

[0699] Preparation of U937 Plasma Membranes

[0700] To prepare plasma membranes, 1×10⁹ U937 cells were harvested fromtheir culture medium by centrifugation at 1000 rpm at 4° C. for 5minutes in a benchtop centrifuge. The cells were resuspended in 40 ml 12mM Tris, pH 7.5, 250 mM sucrose and placed on ice. The cells are thenlysed using a hand-held electric homogenizer (Labortechnik IKAUltra-Turrax) for four, one minute, bursts. To check that cell lysis hadoccurred, 10 μl cell lysate was added to 10 μl Trypan blue and the celllysate was examined under a microscope. After confirming lysis, thehomogenate was centrifuged at 270×g, for 10 minutes at 4° C. to pelletthe nuclear fraction and the supernatant was retained. The supernatantwas centrifuged at 8000×g, 10 mins, 4° C., to pellet the mitochondrialand lysosomal fractions and the supernatant was retained. Thesupernatant was then centrifuged at 100000×g, 60 mins, 4° C. to pelletthe plasma membrane enriched fraction. The supernatant was discarded andthe plasma membrane pellet was resuspended in 1 ml PBS and stored at−70° C. The protein concentration of the plasma membrane fraction wasdetermined using a protein quantification kit (Biorad). Typical yieldswere between 5 and 10 mg of plasma membranes.

[0701] Phage ELISA

[0702] To determine the specificity of each of the unique scFvs, a phageELISA was performed for each scFv against human BLyS, U937 plasmamembranes, TNFα (R&D Systems, Minneapolis, Minn.), BSA and uncoatedwell. Individual E. coli colonies containing a phagemid representing oneof the unique scFvs from panel lwere inoculated into 96-well platescontaining 100 μl 2TYAG medium per well. Plates were incubated at 37° C.for 4 hours, shaking. M13KO7 helper phage was added to each well to aMOI of 10 and the plates were incubated for a further 1 hour at 37° C.The plates were centrifuged in a benchtop centrifuge at 2000 rpm for 10minutes. The supernatant was removed and cell pellets were resuspendedin 100 μl 2TYAK and incubated at 30° C. overnight, shaking. The nextday, plates were centrifuged at 2000 rpm for 10 min and the 100 μlphage-containing supernatant from each well carefully transferred into afresh 96-well plate. Twenty μl of 6×MPBS was added to each well, andincubated at room temperature for 1 hour to pre-block the phage prior toELISA.

[0703] Flexible 96-well plates (Falcon) were coated overnight at 4° C.with human BLyS (1 μg/ml) in PBS, U937 plasma membranes (10 μg/ml) inPBS, TNFα (1 μg/ml) in PBS, BSA (1 μg/ml) in PBS, or PBS. After coating,the solutions were removed from the wells, and the plates were blockedfor 1 hour at room temperature in MPBS. The plates were washed 3 timeswith PBS and then 50 μl of pre-blocked phage was added to each well. Theplates were incubated at room temperature for 1 hour and then washedwith 3 changes of PBST followed by 3 changes of PBS. To each well, 50 μlof an anti-gene VIII-HRP conjugate (Pharmacia) at a 1 to 5000 dilutionin MPBS was added and the plates incubated at room temperature for 1hour. Each plate was washed three times with PBST followed by threetimes with PBS. Then 50 μl of an HRP-labelled anti-mouse polymer (DAKOEnVision) diluted {fraction (1/50)} in 3% MPBS was added and incubatedfor 1 hour at room temperature. Each plate was then washed three timeswith PBST followed by three times with PBS. Fifty μl of TMB substratewas then added to each well, and incubated at room temperature for 30minutes or until colour development. The reaction was stopped by theaddition of 25 μl of 0.5 M H₂SO₄. The signal generated was measured byreading the absorbance at 450 nm (A₄₅₀) using a microtiter plate reader(Bio-Rad 3550).

[0704] The results for 3 clones (I006E07, I008D05 and I016F04) are shownin FIG. 1. All 3 scFvs recognize immobilized BLyS and U937 plasmamembranes but do not recognize TNFα, BSA or an uncoated well (PBS only).These results indicate that these scFvs specifically recognizeimmobilized BLyS and membrane-bound BLyS.

Example 3

[0705] Inhibition in an In Vitro Receptor Binding Assay by Phage ScFvs

[0706] All of the unique phage scFvs in panel 1 were assessed for theirability to inhibit soluble BLyS binding to its cognate receptor on IM9cells.

[0707] Biotinylation of BLyS

[0708] One hundred μg of either human or mouse BLyS was dialysedovernight at 4° C. against 50 mM sodium bicarbonate (sodium hydrogencarbonate) pH8.5 using a slide-a-lyzer cassette (Pierce). The next day,NHS-biotin (Pierce) was dissolved in DMSO to 13.3 mg/ml. This was thenadded to the BLyS at a molar ratio of 20:1 biotin:BLyS, mixed andincubated on ice for 2 hours. The biotinylated BLyS was then dialysedback into sterile PBS (Sigma) using a slide-a-lyzer cassette overnightat 4° C. The biological activity of the biotinylated BLyS was confirmedusing the receptor binding inhibition assay (see below).

[0709] Maintenance of IM9 cells

[0710] IM9 cells are a human B lymphocyte cell line. They weremaintained in RPMI-1640 supplemented with 4 mM L-glutamine, 10% FCS, 10U penicillin, 100 g/ml streptomycin (all reagents from Sigma). The cellsare thawed from frozen stock and can be used in assays after 5 days inculture when they reach a density of 4-8×10⁵ /ml.

[0711] Receptor Binding Inhibition Assay

[0712] Individual E. coli colonies containing a phagemid representingone of the unique scFvs from panel 1 were inoculated into 96-well platescontaining 100 μl 2TYAG medium per well. Plates were incubated at 37° C.for 4 hours, shaking. M13KO7 helper phage was added to each well to aMOI of 10 and the plates were incubated for a further 1 hour at 37° C.The plates were centrifuged in a benchtop centrifuge at 2000 rpm for 10minutes. The supernatant was removed and cell pellets were resuspendedin 100 μl 2TYAK and incubated at 30° C. overnight, shaking. The nextday, plates were centrifuged at 2000 rpm for 10 min and the 100 μlphage-containing supernatant from each well carefully transferred into afresh 96-well plate. Phage were diluted 1 in 2 in MPBS prior to use.

[0713] Flat-bottomed 96-well plates (Costar) were coated with 100 μl perwell of a 1:10 dilution of poly-L-lysine (Sigma) in PBS for 1 hour atroom temperature. The plates were then washed twice with water, allowedto air-dry and placed at 4° C. overnight. One hundred μl of IM9 cells(at 10⁶/ml in RPMI-1640 culture medium) were then added to each well.Plates were then centrifuged at 3200 rpm for 5 mins to pellet the cells.The media was carefully aspirated and 200 μl of MPBS added to each well.The plates were then allowed to block for 1 hour at room temperature.

[0714] To a separate 96-well plate 10 μl of biotinylated BLyS (at 162.5ng/ml) in MPBS was added to each well to give a final concentration of25 ng/ml. Fifty-five μl of each appropriate phage supernatant was addedto each well and the final volume in each well was 65 μl. Plates werethen incubated at room temperature for 30 minutes.

[0715] The IM9 coated plates were washed twice in PBS, tapped dry andimmediately 50 μl of the phage/biotinylated-BLyS mix was added andincubated at room temperature for 1 hour. Plates were washed three timesin PBST and three times in PBS, tapped dry and 50 μl ofstreptavidin-Delfia (Wallac) was added to each well at 1:1000 dilutionin the Manufacturer's assay buffer. The plates were then incubated atroom temperature for 1 hour and washed six times in Delfia wash solution(Wallac). After tapping the plates dry, 100 μl per well of Delfiaenhancement solution (Wallac) was added. The plates were gently tappedto encourage micelle formation, incubated at room temperature for 10minutes, and fluorescence read on a Wallac 1420 workstation at 6520 nM.

[0716] Results for 3 phage scFvs (I001C09, I018D07 and I016H07) thatinhibited the binding of biotinylated BLyS are shown in FIG. 2. Maximalbinding of biotinylated BLyS to its receptor (bio-BLyS only), thebackground signal in the absence of biotinylated BLyS (no bio-BLyS), andresults with an irrelevant (i.e., does not recognize BLyS) phageantibody are also shown. All 3 phage scFvs inhibited biotinylated BLySbinding to its receptor on IM9 cells, identifying these scFvs as scFvsthat bind the soluble form of BLyS. These scFvs also bind to U937membranes, thus they also bind the membrane bound form of BLyS.

[0717] Forty-eight of the scFvs from panel 1 that demonstrated thegreatest inhibition as phage particles in this assay were chosen forfurther study. These 48 scFvs are listed in Table 3. TABLE 3 scFvs thatInhibit the Binding of Biotinylated-BLyS to its Receptor AntibodyAntibody Antibody Antibody Antibody I008C02 I029D07 I008C03 I008C12I028A06 I022E02 I061E07 I007H08 I061H01 I031C03 I018C02 I006D07 I008A11I006D08 I031F02 I008B01 I017D10 I061D02 I026E03 I031F09 I016F04 I007B03I008A09 I027A07 I031G11 I016E05 I018C10 I007F11 I016H07 I050A07 I0018H08I001C09 I037E07 I021B05 I050A12 I018H09 I018D07 I037E12 I031G10 I050B11I029F11 I016F02 I031G08 I051C04 I022D01 I031C07 I003F12 I012A06

Example 4

[0718] Specificity of Anti-BLyS Antibodies

[0719] The specificity of the 48 scFvs listed in Table 3 for human andmurine BLyS was determined using phage ELISA.

[0720] Phage ELISA

[0721] To determine the specificity of the 48 scFvs, a phage ELISA wasperformed against human and mouse BLyS, and a panel of related andunrelated human antigens: Fas ligand, TRAIL, TNFα, TNFβ, and PBS. The:Fas ligand, TRAIL, TNFα, and TNFβ antigens were obtained from R&DSystems, Minneapolis, Minn. Individual E. coli colonies containingphagemid were inoculated into 5 ml 2YTAG and incubated at 37° C. for 4hours, shaking. M13KO7 helper phage (Pharmacia) was added to each tubeto a MOI of 10 and incubated for 30 minutes at 37° C. for 1 hour, thefirst 30 minutes static and the final 30 minutes with gentle shaking.Cells were pelleted by centrifugation at 3,500 rpm for 10 minutes andthe supernatant discarded. Cell pellets were resuspended in 5 ml 2TYAKand incubated at 30° C. overnight with shaking. The next day, the cellswere pelleted by centrifugation at 3,500 rpm for 10 minutes. Thephage-containing supernatant (5 ml) was carefully transferred to a freshtube, 1 ml of 6MPBS was added, and the tube was incubated at roomtemperature for 1 hour to pre-block the phage prior to ELISA.

[0722] All antigens were coated at 1 μg/ml. ELISAs were performedessentially as described in Example 2. The only exception to this beingthe detection of phage antibody binding to mouse BLyS where the stepinvolving incubation with the HRP-labelled anti-mouse polymer wasomitted. Binding to mouse BLyS was detected with TMB as in SectionExample 2.

[0723] All 48 scFvs are specific for immobilized human BLyS and 43 outof the 48 scFvs cross-react with immobilized mouse BLyS but not with anyother unrelated or related antigen tested. I008C03, I007F11, I037E07,I037E12, and I016H07 did not bind murine BLyS. Results for two scFvs,I022D01 and I031F02, are shown in FIG. 3. Both these scFvs specificallyrecognize human and mouse BLyS but not any other unrelated or relatedantigen tested.

Example 5

[0724] Specificity for the Membrane-Bound Form of BLyS

[0725] The specificity of 48 scFvs for membrane-bound BLyS wasdetermined by the phage ELISA described in Example 2. BLyS wasimmobilised onto plastic as a membrane-bound form present on plasmamembranes preparations from the human macrophage-like cell line, U937.This cell line is known to express the membrane-bound form of humanBLyS.

[0726] To demonstrate that this binding is specific for membrane-boundBLyS, a competition ELISA was developed to determine if the ELISA signalfor an individual antibody on U937's could be competed out bypre-incubation with either BLyS or TNFα. An anti-BLyS antibody that alsorecognizes membrane-bound BLyS would be expected to demonstrate a signalreduction with free BLyS but not free TNFα.

[0727] Competition ELISA

[0728] Individual E. coli colonies containing phagemid for each of the48 scFvs listed in Table 3 were inoculated into 5 ml 2YTAG and incubatedat 37° C. for 4 hours, shaking. M13KO7 helper phage (Pharmacia) wasadded to each tube to a MOI of 10 and incubated for 30 minutes at 37° C.for 1 hour, the first 30 minutes static and the final 30 minutes withgentle shaking. Cells were pelleted by centrifugation at 3,500 rpm for10 minutes and the supernatant discarded. Cell pellets were resuspendedin 5 ml 2TYAK and incubated at 30° C. overnight with shaking. The nextday, the cells were pelleted by centrifugation at 3,500 rpm for 10minutes. The phage-containing supernatants (5 ml) were carefullytransferred to a fresh tube.

[0729] For each of the 48 scFvs listed in Table 3, two aliquots of 20 μl6×MPBS were pipetted into separate wells of a 96-well plate (Greiner).The first aliquot was supplemented with BLyS to a final concentration of0.5 μg/ml. The second aliquot was supplemented with TNF-α to a finalconcentration of 0.5 μg/ml. Each experiment was performed in triplicate.One hundred μl of each phage supernatant was then added to each aliquotand mixed by pipetting up and down. The phage were incubated (±competingantigen) at room temperature for 1 hour.

[0730] Flexible 96-well plates (Falcon) were coated overnight at 4° C.with 50 μl of 10 μg/ml U937 plasma membranes. After coating, the plateswere washed 3 times with PBS and blocked for 1 hour at room temperaturewith 200 μl MPBS. The plates were washed 3 times with PBS and 50 μl ofphage (±competing antigen) was added to each appropriate well. Theplates were incubated at room temperature for 1 hour and then washedwith 3 changes of PBST followed by 3 changes of PBS. To each well, 50 μlof a mouse anti-gene VIII-HRP conjugate (Pharmacia) at a 1:5000 dilutionin MPBS was added and the plates incubated at room temperature for 1hour. Each plate was washed three times with PBST followed by threetimes with PBS. Then 50 μl of an HRP-labelled anti-mouse polymer (DAKOEnVision) diluted 1:50 in 3% MPBS was added and incubated for 1 hour atroom temperature. Each plate was then washed three times with PBSTfollowed by three times with PBS. Fifty μl of TMB substrate was thenadded to each well, and incubated at room temperature for 30 to 60minutes or until color development. The reaction was stopped by theaddition of 25 μl of 0.5 M H₂SO₄. The signal generated was measured byreading the absorbance at 450 nm (A₄₅₀) using a microtiter plate reader(Bio-Rad 3550).

[0731] All 48 scFvs bind to U937 plasma membrane preparations. Thissignal could be competed out by pre-incubation of the phage antibodywith BLyS but not by pre-incubation with TNF-α. This indicates that the48 scFvs specifically recognize membrane-bound BLyS as well as solubleBLyS. Typical results are exemplified by scFvs I031F09, I050A12 andI051C04 and are shown in FIG. 4. All 3 scFvs demonstrate binding to U937plasma membranes. This binding was specifically competed out with BLySbut did not compete with TNF-α, demonstrating specific recognition ofmembrane-bound BLyS.

Example 6

[0732] scFv Off-rate Determinations

[0733] All off-rate determinations were performed on BLAcore 2000machines, using the BIAcore 2000 Control Software and evaluated usingthe BIAevaluation 3.0 software.

[0734] Preparation of a Low Density BLyS Surface

[0735] A 500RU surface was prepared for kinetic studies with purifiedscFvs. A low density BLyS surface (500 RU BLyS coupled) was prepared inflow cell 2 by amine coupling to a CM5 chip. A new CM5 chip was insertedinto the BIAcore and a sensorgram initiated with HBS buffer at a flowrate of 5 μl/min. The NHS and EDC coupling solutions (BIAcore) weremixed according to manufacturer's instructions and 30 μl injected overthe CM5 surface. Fifty μl of BLyS at 1 μg/ml in 10 mM sodium acetatebuffer, pH4, was then injected followed by 30 μl of ethanolamine-HClsolution (BIAcore). The flow rate was then adjusted to 20 μl/min and 10μl of 4M guanidine hydrochloride in HBS injected over the surface. Thisstrips the surface of non-covalently bound BLyS.

[0736] Measurement of scFv Off-rate Kinetics on the Low Density Surfaces

[0737] The chip containing the low density BLyS surface was inserted into the BLAcore. A dilution series of purified scFvs was prepared in HBS,typically 50 μg/ml doubling dilutions down to 1.5 ug/ml. The dilutionseries was then injected sequentially over the low density BLyS surface(and blank control) using the following program: MAIN FLOWCELL 1,2,3,4APROG genab r1d1 ab1 APROG genab r1d2 ab2 APROG genab r1d3 ab3 APROGgenab r1d4 ab4 APROG genab r1d5 ab5 APROG genab r1d6 ab6 APPEND CONTINUEEND DEFINE APROG genab PARAM %Abpos %AbId FLOW 20 KINJECT %Abpos 200 80INJECT r1c6 10!guanidine hydrochloride regenera- tion step EXTRACLEANEND

[0738] Bound scFvs were removed by injecting 10 μl 4M GuHCl in HBS overthe surface between scFv samples.

[0739] The binding curves for individual scFvs were analyzed using theBIAevaluation software to determine antibody off-rates. Kinetic analysisfor a typical scFv antibody, I003C02, is shown in FIG. 5. I003C02 has aK_(off)=6×10⁻³ s⁻¹.

Example 7

[0740] Inhibition in an In Vitro Receptor Binding Assay by scFvAntibodies

[0741] The 48 scFvs listed in Table 3 were purified and assessed fortheir ability to inhibit BLyS binding to its receptor on IM9 cells.

[0742] Purification of scFv

[0743] To determine the inhibitory potency of anti-BLyS scFv, scFv'swere first prepared by IMAC. 2TYAG (5 ml) was inoculated with a singlecolony and grown overnight at 30° C., shaking. This overnight culturewas then used to inoculate 500 ml of 2TY containing 100 μg/ml ampicillinand 0.1% Glucose, and grown at 30° C., shaking, until an A₆₀₀ of 1.0 wasattained. IPTG was added to 1 mM and the culture was grown for a further3.5 hours at 30° C.

[0744] Cells were harvested by centrifugation at 5,000 rpm, andresuspended in 10 ml of TES. A further 15 ml of a 1:5 dilution (inwater) of TES was added, and the cell suspension incubated on a turningwheel at 4° C. for 30 minutes. This causes osmotic shock and yields aperiplasmic extract containing the scFv. Residual cells and debris werepelleted by centrifugation at 9,000 rpm for 20 minutes at 4° C. Thesupernatant was transferred to a new tube, and 50 μl of 1 M MgCl₂ added.Two ml of a Ni-NTA agarose (Qiagen), pre-washed with buffer (50 mMsodium phosphate, pH 8, 300 mM NaCl) together with a protease inhibitortablet (Boehringer Mannheim) were then added to the periplasmic extract.The preparation was incubated, rotating, overnight at 4° C. The Ni-NTAwas pelleted by centrifugation at 2,000 rpm for 5 minutes, and thesupernatant was aspirated. The agarose beads were washed 3 times with 50ml wash buffer, centrifuging to collect the agarose in between eachwash. Ten ml of wash buffer was added after the final wash, and theslurry was loaded on to a polyprep column (BioRad). Two ml elutionbuffer (50 mM NaPi (sodium phosphate), pH 8, 300 mM NaCl, 250 mMimidazole) was added to the drained agarose, and the eluate wascollected. IMAC purified scFv was buffer exchanged in to PBS by use of aNap 5 column (Pharmacia) according to the manufacturer's instructions.The A₂₈₀ was read and the protein concentration determined using a molarextinction coefficient of 1 mg/ml protein=A₂₈₀ 1.4. Purified scFv wasstored in 500 μl aliquots at −70° C.

[0745] Receptor Binding Inhibition Assay

[0746] Flat-bottomed 96-well plates (Costar) were coated with 100 μl perwell of a 1:10 dilution of poly-L-lysine (Sigma) in PBS for 1 hour atroom temperature. The plates were then washed twice with water, allowedto air-dry and placed at 4° C. overnight. One hundred μl of IM9 cells(at 10⁶/ml in RPMI-1640) were then added to each well. Plates were thencentrifuged at 3200 rpm for 5 mins to pellet the cells. The media wascarefully aspirated and 200 μl of MPBS added to each well. The plateswere then left to block for 1 hour at room temperature.

[0747] To a separate 96-well plate, titrate test scFvs in MPBS, intriplicate, over a concentration range from 10 μg/ml down to 0.001 μg/mlwere added. The final volume of test scFv in each well was 55 μl.Competition with unlabelled BLyS was also included in every assay as acontrol. Unlabelled BLyS, in MPBS, was typically titrated in triplicate,over a concentration range from 1 μg/ml down to 0.001 μg/ml. 10 μl ofbiotinylated-BLyS (at 162.5 ng/ml) in MPBS was added to each well togive a final concentration of 25 ng/ml. Plates were then incubated atroom temperature for 30 minutes.

[0748] The IM9 coated plates was washed twice in PBS, tapped dry andimmediately 50 μl of the scFv/biotinylated-BLyS mix was added andincubated at room temperature for 1 hour. Plates were washed three timesin PBST and three times in PBS, tapped dry and 50 μl per well added ofstreptavidin-Delfia (Wallac) at 1:1000 dilution in the Manufacturer'sassay buffer. The plates were then incubated at room temperature for 1hour and washed six times in Delfia wash solution (Wallac). Aftertapping the plates dry, 100 μl per well of Delfia enhancement solution(Wallac) was added. The plates were gently tapped to encourage micelleformation, incubated at room temperature for 10 minutes, andfluorescence read on a Wallac 1420 workstation at 6520 nM.

[0749] Typical titration curves for two scFv antibodies, I007F11 andI050A07, are shown in FIG. 6. Unlabelled BLyS competed for binding toits receptor with an IC₅₀ value of 0.8 nM. The IC₅₀ values for I007F11and I050A07 are 7.9 nM and 17.1 nM, respectively. The assay wasperformed in triplicate and standard error bars are shown. The 9 scFvsthat demonstrated the greatest inhibition as scFv are listed in Table 4.This data also confirms that these9 scFvs recognize the soluble form ofBLyS. TABLE 4 ScFvs that demonstrated greatest potency in BLyS ReceptorBinding Inhibition Assay ScFv Antibody I017D10 I022D01 I008A11 I006D08I031F02 I050A12 I050B11 I051C04 I003F12S

Example 8

[0750] Antibodies Recognizing a Soluble Form of BLyS

[0751] A library of phage was screened in an assay to identify thosephage displaying scFvs that immunospecifically bind to the soluble butnot the membrane-bound forms of BLyS.

[0752] A phage library was screened for the ability to bind tobiotinylated BLyS. The phage were exposed to biotinylated BLyS, allowedan interval of time to bind the biotinylated BLyS. Phage bindingbio-BLyS were then isolated by capture on streptavidin coated magneticbeads.

[0753] The phage identified in the screen above (capture of Bio-BLySfrom solution) were then screened by ELISA for their ability to bindimmobilized BLyS. The scFv expressed by phage that bound immobilizedBLyS were then cloned and sequenced. Again, several sequences wereidentified multiple times, thus a panel (panel 2) consisting of onexample of each phage expressing a unique scFv was then characterizedfurther.

[0754] The derived amino acid sequences of these scFvs are shown inTable 1 above. The individual V_(H) and V_(L) segments of the scFvs werealigned to the known human germline sequences in V-BASE (Tomlinson etal, www.mrc-cpe.cam.ac.uk) and the closest germline identified.

Example 9

[0755] Specificity For Soluble BLyS

[0756] The scFvs were isolated from a library of phage based on theirability to bind a soluble form of BLyS. Briefly, phage were preincubatedwith biotinylated BLyS in solution. Phage that bound to thisbiotinylated BLyS were then isolated using streptavidin coated magneticbeads.

[0757] The specificity of each of the unique scFvs for BLyS and for themembrane-bound form of BLyS, was determined by phage ELISA. BLyS wasimmobilised onto plastic as a purified soluble form of the protein or asa membrane-bound form present on plasma membrane preparations from thehuman macrophage-like cell line, U937. Maintenance of U937 cells andplasma membrane preparations were performed as detailed in Example 2.

[0758] Phage ELISA

[0759] To determine the specificity of each of the scFvs, a phage ELISAwas performed for each antibody against human BLyS, U937 plasmamembranes, TNFα, BSA and an uncoated well. Antigen coating conditionswere as described in Example 2, apart from human BLyS. BLyS was firstbiotinylated (as described in Example 3) and coated at 1 μg/ml ontostreptavidin coated plates (Reacti-Bind, Pierce) for 30 mins at roomtemperature. The plates were then washed, blocked and the phage ELISAperformed as detailed in Example 2.

[0760] The results for 3 clones (I074B12, I075F12 and I075A02) that bindthe soluble but not the membrane-bound form of BLyS are shown in FIG. 7.As a control, a phage antibody that recognizes TNFα, is also shown inFIG. 7. There is a small non-specific background signal on the U937plasma membranes that is evident with both the anti-BLyS scFvs as wellas the anti-TNFα, control. All 3 anti-BLyS scFvs recognize BLyS but notU937 plasma membranes, TNFα, BSA or an uncoated well (PBS only). Thisindicates that the scFvs do not bind the membrane-bound form of BLyS.Further, The fact that these scFvs were isolated on the basis of theirability to bind soluble biotinylated BLyS indicates that they bind thesoluble form of BLyS. Further confirmation of these scFvs′ specificityfor BLyS is provided in Example 10.

Example 10

[0761] Inhibition in an In Vitro Receptor Binding Assay by Phage scFvs

[0762] All of the unique phage scFvs from panel 2 were assessed fortheir ability to inhibit BLyS binding to its cognate receptor on IM9cells. The biotinylation of BLyS, maintenance of IM9 cells and receptorbinding inhibition assay were performed as described in Example 3.

[0763] Results for two phage scFvs, I0025B09 and I026C04 are shown inFIG. 8. Maximal binding of biotinylated BLyS to its receptor (bio-BLySonly), the background signal in the absence of biotinylated BLyS (nobio-BLyS), and results with an irrelevant (i.e. does not recognize BLyS)phage antibody are also shown. Both phage scFvs inhibited biotinylatedBLyS binding to its receptor on IM9 cells. 33 of the unique scFvs frompanel 2 were identified for further study. These 33 scFvs demonstratedthe greatest inhibition as phage particles in this assay and are listedin Table 5. TABLE 5 Identification of 33 phage scFvs to free BLyS thatdemonstrates the most significant inhibition of biotinylated-BLySbinding to its receptor Antibody Antibody Antibody Antibody I026C04I074B12 I073F04 I065D04 I003C06 I075A02 I078D08 I068C08 I025B09 I068B08I078D02 I068F03 I027B12 I068B04 I075G01 I069B07 I025B06 I068C06 I071B03I030A10 I075F12 I072B09 I002A01R I065D08 I078H08 I002A01K I065F08I064C04 I026C04R I067B10 I064C07 I026C04K I067F05

Example 11

[0764] Specificity of Anti-BLyS scFvs

[0765] The specificity of the 33 scFvs (listed in Table 5) forimmobilized human and murine BLyS was determined using phage ELISA.

[0766] Phage ELISA

[0767] To determine the specificity of the 33 scFvs, a phage ELISA wasperformed as described in Example 4 against human and mouse BLyS, and apanel of related human antigens: TRAIL, LIGHT, TNFα, TNFβ, and anuncoated well (PBS only).

[0768] Typical results for two scFvs, I067F05 and I078D02 are shown inFIG. 9. A control antibody that specifically recognizes TNFα is alsoshown. Both anti-BLyS scFvs specifically recognize immobilized human andmouse BLyS but not any other antigen tested.

[0769] All 33 scFvs are specific for human BLyS. 14/33 cross-react withmouse BLyS but not with any other unrelated or related antigen tested.

Example 12

[0770] scFv Off-Rate Determinations

[0771] Off-rate determinations, preparation of a low density BLySsurface and kinetic measurements were as detailed in Example 6.

[0772] The binding curves for individual scFvs were analysed using theBIAevaluation software to determine antibody off-rates. Kinetic analysisfor a typical scFv antibody, I002A01, is shown in FIG. 10. I002A01 has aK_(off)=9×10⁻⁴ s⁻¹.

Example 13

[0773] Inhibition in an In Vitro Receptor Binding Assay by scFvAntibodies

[0774] The 33 scFvs identified in Table 5 were prepared as purifiedscFvs and assessed for their ability to inhibit BLyS binding to itsreceptor on IM9 cells. The scFvs were purified and analysed in thereceptor binding inhibition assay as described in Example 6.1.8.

[0775] Typical titration curves for two scFvs, I0068C06 and I074B12, areshown in FIG. 11. Unlabelled BLyS competed for binding to its receptorwith an inhibitory constant 50 (IC₅₀) value of 0.66 nM. The IC₅₀ valuesfor I0068C06 and I074B12 are 61 nM and 13 nM, respectively. The assaywas performed in triplicate and standard error bars are shown. The 7scFvs that demonstrated the greatest inhibition as scfv are listed inTable 6. TABLE 6 Identification of 7 scFvs to free BLyS that demonstratethe most signifi- cant inhibition of biotinylated-BLyS binding to itsreceptor as purified scFv's. Antibody I002A01-R I002A01-K I026C04-RI026C04-K I068C06 I075F12 I067B10

Example 14

[0776] ScFvs Recognizing Membrane-bound BLyS

[0777] A library of phage was screened in an assay to identify thosephage displaying scFvs that immunospecifically bind to themembrane-bound but not the soluble form of BLyS.

[0778] As a starting point, a library of phage expressing scFvantibodies were panned on immobilized HIS-tagged BLyS. Phage isolated bypanning were then screened for the ability to bind to HIS-tagged BLyS.HIS-tagged BLyS was obtained by expressing amino acids 71-285 of SEQ IDNO:3228 using the pQE9 vector (Qiagen Inc., Valencia, Calif.) in E. coliand purifyng the expressed protein. This phage clones identified by thisscreen were then sequenced. After sequencing, A panel (panel 3) of phageeach expressing a unique scFv that bound HIS-tagged BLyS was generatedand further characterized.

[0779] The derived amino acid sequences of the unique scFvs from panel 3are shown in Table 1 above. The individual V_(H) and V_(L) segments ofthe scFvs were aligned to the known human germline sequences in V-BASE(Tomlinson et al, www.mrc-cpe.cam.ac.uk) and the closest germlineidentified.

Example 15

[0780] Recognition of Membrane-bound BLyS

[0781] The specificity of each of the unique scFvs for both themembrane-bound form of BLyS as well as for the soluble form of BLyS, wasdetermined by phage ELISA.

[0782] BLyS was immobilised onto plastic either directly as a purifiedsoluble form of the protein or biotinylated and coated on a streptavidinplate as in Example 9. Binding to HIS-tagged BLyS was used as a primaryscreen for scFv's that would bind the membrane-bound form of BLyS (seebelow). The membrane-bound form of BLyS was presented as plasmamembranes preparations from the human macrophage-like cell line, U937 orthe murine cell line P388.

[0783] Mouse monoclonal antibodies have been raised against His-taggedBLyS according to standard procedures. Characterization of these mousemonoclonal antibodies revealed that they specifically recognized bothHis-tagged BLyS and the membrane-bound form of BLyS on U937 cells, butnot soluble BLyS. Therefore, specific recognition of His-tagged BLyS wasused as supporting evidence for the recognition of the membrane-boundform of BLyS by phage and scFv antibodies.

[0784] Phage ELISA

[0785] To determine the specificity of each of the scFvs, a phage ELISAwas performed for each antibody against His-tagged human BLyS, U937plasma membranes, TNFα, BSA and an uncoated well. Antigen coatingconditions were as described in 2. apart from human BLyS. BLyS was firstbiotinylated (as described in Example 3) and coated at 1 μg/ml ontostreptavidin coated plates (Reacti-Bind, Pierce) for 30 mins at roomtemperature. The plates were then washed, blocked and the phage ELISAperformed as detailed in Example 2.

[0786] The results for 3 clones, I079C01, I081C10 and I082A02, and acontrol phage antibody that recognizes TNFα, are shown in FIG. 12. All 3scFvs recognize U937 plasma membranes (U937) and His-tagged BLyS(HIS-BLyS) but not, biotinylated BLyS (bio-BLyS) or an uncoated well(PBS). This indicates that the scFvs recognize the membrane-bound formof BLyS.

Example 16

[0787] Specificity for Membrane-bound BLyS

[0788] The specificity of the scFvs for only the membrane-bound form ofBLyS, and not for the soluble form, was confirmed using a competitionELISA. This assay assesses the ability of test phage scFvs to bind tothe membrane-bound form of BLyS on U937 plasma membranes in the presenceof different forms of competing BLyS. Competing BLyS was either theHis-tagged form of BLyS or soluble BLyS. ScFvs specific for themembrane-bound BLyS would be expected to be competed out bypre-incubation with His-tagged BLyS but not by pre-incubation withsoluble BLyS.

[0789] Maintenance of U937 cells and plasma membrane preparations wereperformed as detailed in Example 2.

[0790] Competition ELISA

[0791] U937 plasma membranes (50 per well ) were coated at 10 μg/ml inPBS onto Falcon 96-well plates overnight at 4° C.

[0792] Individual E. coli colonies containing a phagemid representingone of the unique scFvs from the panel 3 were inoculated into 50 mltubes (Falcon) containing 5 ml 2TYAG medium. Tubes were incubated at 37°C. for 4 hours, shaking. M13KO7 helper phage was added to each tube toan MOI of 10 and the tubes were incubated for a further 1 hour at 37° C.The tubes were centrifuged in a benchtop centrifuge at 3500 rpm for 10minutes. The supernatant was removed and cell pellets were resuspendedin 5 ml 2TYAK and incubated at 30° C. overnight, shaking. The next day,tubes were centrifuged at 3500 rpm for 10 min and the phage-containingsupernatant carefully transferred into a fresh tube.

[0793] For each test phage antibody, 3 aliquots of 20 μl 18%marvel/6×PBS were transferred into separate wells of a 96-well plate.The first aliquot was supplemented with His-tagged BLyS to a finalconcentration of 60 μg/ml. The second aliquot was supplemented withsoluble BLyS to a final concentration of 60 μg/ml. The third aliquot wasnot supplemented with any competing antigen. One hundred μl of phagesupernatant was then added to each aliquot and left to block at roomtemperature for 1 hour.

[0794] The antigen-coated plates were washed once with PBS before theaddition of 200 μl/well 3% marvel/PBS. These plates were left to blockat 37° C. for 1 hour and were then washed once with PBS. Duplicatesamples of 50 μl pre-blocked phage (above) were added to theantigen-coated plates and left at room temperature for 1 hour. Plateswere washed 3× with PBS/0.1% Tween 20, then 3× with PBS. Fifty μl/wellmouse anti-M13 HRP (Pharmacia) at 1/5000 in 3% Marvel/PBS was added andleft for 1 hour at room temperature. Plates were washed 3 times withPBS/0.1% Tween 20, then 3 times with PBS. Fifty μl/well HRP-labelledanti-mouse Envision polymer (DAKO) at 1/50 in 3% marvel/PBS was addedand left for 1 hour at RT. Plates were washed 3 times with PBS/0.1%Tween 20, then 3 times with PBS. Next, 50μl/well of TMB (Sigma) wasadded and plates left to develop for 30 to 60 minutes. When sufficientcolor has developed, 25 μl/well 0.5M H₂SO₄ was added to stop thereaction. The plates were read at 450 nm on a microtiter plate reader(Bio-Rad 3550).

[0795] The results for 3 clones, I079B04, I079F08 and I080B01, and acontrol phage antibody that recognizes TNFα, are shown in FIG. 13. All 3scFvs recognize U937 plasma membranes (U937). This binding is competedout to background levels (i.e. comparable to the signal observed withthe anti-TNFα phage antibody) in the presence of His-tagged BLyS(HIS-BLyS) but not biotinylated BLyS (bio-BLyS). This confirms that thescFvs specifically recognize the membrane-bound form but not the solubleform of BLyS.

Example 17

[0796] High Throughput BIAcore Screen to Identify High Affinity scFvs

[0797] This is a 96-well screen where the test samples (scFvs) arederived from 1 ml periplasmic extracts of individual antibody expressingclones. Potentially higher affinity scFvs are then identifiedprincipally as those giving a large number of total RU's bound to aHIS-BLyS surface in BIAcore. This method of ranking does assumeapproximately equal yields of scFv from each clone. Since this is notalways the case, some scFvs may also be identified that simply expresshigh levels of scFv. These can be discriminated from those of higheraffinity by further characterization of the scFvs (see Example 18).

[0798] Preparation of ScFv from 1 ml E. coli Cultures

[0799] Individual E. coli colonies containing a phagemid representingone of the unique scFvs from panel 3 were inoculated into 96-well platescontaining 100 μl 2TYAG medium per well. Eight wells on each plate werereserved for positive and negative control samples. The plate was grownovernight at 30° C. with shaking at 120 rpm.

[0800] Next day, 1 ml of 2TYAG+345 mM sucrose was added to each well ofan autoclaved 96 deep well plate (Beckman). Twenty μl of each overnightculture was resuspended and transferred to the appropriate well of thedeep well plate. The plate was grown for approximately 3.5 hours at 30°C. with shaking at 250 rpm (or until the OD₆₀₀=0.6). Fifty μl of 1M IPTGwas added to 5 ml 2TY and 10 μl of this was added to each well. Theplate was grown overnight at 30° C. with shaking at 250 rpm.

[0801] Plates were kept at 4° C. for the remainder of the procedure. Theovernight plate (above) was centrifuged at 3500 rpm for 10 minutes at 4°C. to pellet the cells. The supernatant was decanted and each pelletresuspended in 100 μl TES (0.2M Tris HCl pH8.0, 0.5 mM EDTA, 0.5Msucrose) and transferred to a fresh 96 well plate. This plate wasincubated on ice for 30 minutes and then centrifuged for 10 minutes at3500 rpm at 4° C. to pellet the cell debris. During centrifugation, 15μl of freshly made protease inhibitors cocktail (Roche, 1 tabletdissolved in 1.5 ml water) was added to each well of a fresh 96 wellplate. Supernatants from the centrifuged plate were then transferred tothe plate containing the protease inhibitors. The plate was centrifugedat 3500 rpm for 10 minutes at 4° C. and the supernatant was transferredto a further 96-well plate. This step was repeated at least once more oruntil there was no sign of any cell debris following centrifugation.Finally, the plate was covered in foil to prevent evaporation of samplesduring the BIAcore run.

[0802] Generation of a High Density HIS-BLyS Surface

[0803] All BIAcore analysis was performed on BIAcore 2000 machines,using the BIAcore 2000 control software and evaluated using theBIAevaluation 3.0 software. A high density His-tagged BLyS surface(>1000 RU HIS-BLyS coupled) was prepared in flow cell 2 by aminecoupling to a CM5 chip. A new CM5 chip was inserted into the BIAcore anda sensorgram started over flow cell 2 with HBS buffer at a flow rate of5 μl/min. The NHS and EDC solution were mixed 1:1 before injecting 30μlover the CM5 surface. Fifty μl HIS-BLyS (at 10 μg/ml in Sodium acetatebuffer, pH4) was injected and allowed to couple to the surface. Thirtyμl of ethanolamine-HCl solution was then injected to block free NHSesters. Prior to using the chip, 10 μl of 4M Guanidine hydrochloride inHBS was injected over the surface to strip the surface of non-covalentlybound BLyS. A blank surface (no HIS-BLyS) was also prepared over flowcell 1 so that non-specific binding effects can be subtracted from theHIS-BLyS binding curves.

[0804] Typically, a 5000 RU His-tagged BLyS surface was generated inthis way and used for 96-well analysis of scFvs isolated from theperiplasm of E. coli.

[0805] BIAcore Analysis

[0806] The 96-well plate containing periplasmic scFvs was secured insidethe BIAcore. Two ml of 4M Guanidine hydrochloride in HBS was placed in arack inside the BIAcore for regeneration of the HIS-BLyS surface betweensamples. The sensorgram was run over flow cells 1 and 2 at a flow rateof 20 μl/minute. The following method was run: MAIN FLOWCELL 1,2,3,4LOOP cycle STEP APROG inj %pos ENDLOOP APPEND CONTINUE END DEFINE LOOPcycle LPARAM %pos r1a1 r1b1 r1c1 r1d1 r1e1 r1f1 etc (all wells listeduntil r1h12) END DEFINE APROG inj PARAM %pos FLOW 20 KINJECT %pos 35 30!scfv injection QUICKINJECT r2f3 10 !regeneration EXTRACLEAN END

[0807] When the run had finished, the sensorgram data for flow cell 1was subtracted from the data for flow cell 2 for each sample using theBIAevaluation software. The clones were compared with one anotherprincipally by overall RU change as the scFv dissociates from thesurface. In addition a few scFvs were identified as having potentiallyslower off-rates. An example of the dissociation section of a typicalsensorgram for 8 scFvs is shown in FIG. 14. An anti-TNFα antibody thatdoes not recognize BLyS was included as a control. Of the 8 scFvsexemplified, I079F06 was identified for further study due to therelatively high numbers of RU's bound to the surface.

[0808] ScFvs were identified principally if they demonstrated a RUchange of over 1200, a few were also identified as having potentiallyslower than typical off-rates. A total of 28 clones were chosen on thesecriteria and are listed in Table 7. TABLE 7 Identification of 28antibodies to membrane-bound BLyS that demonstrate the most significantRU changes by BIAcore Antibody Antibody I079C01 I084C04 I082H08 I080E05I079E02 I083B12 I079B05 I082G01 I079F06 I082G02 I079F06 I082C03 I079F11I082A05 I079B12 I082D07 I080B01 I082B08 I080G09 I084A01 I099D03 I084B02I080D03 I080A08 I080A03 I084C11 I083G03 I080G07

Example 18

[0809] scFv Affinity Determinations

[0810] The affinity (K_(D)) of the 28 scFvs was determined using theBIAcore.

[0811] Low Density HIS-BLyS Surface for Kinetic Studies

[0812] 500RU surfaces were used for kinetic studies of purified scFvbinding to HIS-BLyS. The method to prepare these surfaces was identicalto the method described in Example 17, only smaller volumes of HIS-BLySwere injected.

[0813] Measurement of scFv Binding Kinetics

[0814] The chip containing the low density HIS-BLyS surface was insertedinto the BIAcore. A dilution series for each of the 28 purified scFvs(prepared as in Example 6) were diluted in HBS (typically starting with50 μg/ml scFv and double diluting down to 1.5 μg/ml). The dilutionseries was then injected sequentially over the blank control (flowcell 1) and low density HIS-BLyS surface (flow cell 2) using thefollowing program: MAIN FLOWCELL 1,2,3,4 APROG genab r1d1 ab1 APROGgenab r1d2 ab2 APROG genab r1d3 ab3 APROG genab r1d4 ab4 APROG genabr1d5 ab5 APROG genab r1d6 ab6 APPEND CONTINUE END DEFINE APROG genabPARAM %Abpos %AbId FLOW 20 KINJECT %Abpos 200 80 INJECT r2f3 10EXTRACLEAN END

[0815] Bound scFv were removed by injecting 10 μl of 4M Guanidinehydrochloride in HBS (location r2f3 in the above program) over thesurface between samples. Binding curves for individual scFv wereanalysed using the BIAevaluation software to determine antibody on- andoff-rates.

[0816] A typical example of the binding curves generated for the scFvantibody I082C03 is shown in FIG. 15. The off-rate for this clone wascalculated as 2×10⁻³ s⁻¹. The affinity of I082C03 was calculated as 20nM, assuming 100% activity of the scFv. The 5 scFvs with the highestaffinities as scFvs are given in Table 8. TABLE 8 Identification of 5antibodies to membrane-bound BLyS that have the highest affinities asscFvs Affinity Antibody (K_(D)) I079F11  5 nM I079E02 10 nM I082G02  6nM I082H08  1 nM I099D03  4 nM

Example 19

[0817] Recognition of Mouse Membrane-Bound BLyS

[0818] The ability of the 5 scFvs listed in Table 8 to also recognizemurine membrane-bound BLyS was determined using a competition ELISA.This assay assesses the ability of test phage scFvs to bind to themembrane-bound form of BLyS on the murine cell line, P388, plasmamembranes in the presence of different forms of competing human BLyS.Competing BLyS was either presented as the His-tagged form of BLyS, orsoluble BLyS. ScFvs that recognize mouse membrane-bound BLyS would givean ELISA signal on the P388 plasma membranes that is competed out bypre-incubation with HIS-tagged BLyS but not by pre-incubation withsoluble BLyS.

[0819] Maintenance of P388.D1 Cells and Preparation of Plasma Membranes

[0820] P388.D1 cells are a mouse monocyte-macrophage like cell line.They were cultured in L-15 medium supplemented with 2mM L-glutamine, 10%CS, 10 U penicillin, 100 g/ml streptomycin (all reagents from Sigma).Cells were split 1:4 every 3-4 days to maintain a cell density of2-8×10⁵ per ml. A fresh aliquot of cells was thawed from liquid nitrogenevery 6 weeks. Plasma membrane fractions were prepared as described inExample 2.

[0821] Competition ELISA

[0822] P388 plasma membranes (50 μl per well) were coated at 10 82 g/mlin PBS onto Falcon 96-well plates overnight at 4° C. The method isotherwise essentially as described Example 16.

[0823] The results for 3 clones, I079E02, I082H08 and I099D03 are shownin FIG. 16. All 3 scFvs recognize P388 plasma membranes. This binding iscompeted out in the presence of HIS-tagged BLyS (HIS-BLyS) but not inthe presence of biotinylated BLyS (bio-BLyS). This confirms that thesescFvs also recognize the membrane-bound form but not the soluble form ofmouse BLyS.

Example 20

[0824] Conversion of scFvs to IgG1 Format

[0825] The VH domain and the VL domains of scFvs that we wished toconvert into IgG molecules were cloned into vectors containing thenucleotide sequences of the appropriate heavy (human IgGI) or lightchain (human kappa or human lambda) constant regions such that acomplete heavy or light chain molecule could be expressed from thesevectors when transfected into an appropriate host cell. Further, whencloned heavy and light chains are both expressed in one cell line (fromeither one or two vectors), they can assemble into a complete functionalantibody molecule that is secreted into the cell culture medium. Methodsfor converting scFvs into conventional antibody molecules are well knownwithin the art.

[0826] Generation of NS0 Cell Lines Expressing Anti-BLyS Antibodies(IgG1)

[0827] Plasmids containing the heavy and light chains were separatelylinearized using the Pvu I restriction enzyme. The linearized DNAs werepurified by phenol-chloroform extraction followed by ethanolprecipitation and then resuspended in H₂O. NS0 cells (10⁷) from agrowing culture were electroporated (0.25 kV and 975 μF) in PBS with12.5 μg linearized heavy chain plasmid DNA and 37.5 μg linearized lightchain DNA. The cells were washed in 20 ml non-selective medium (10% FCSin DMEM supplemented with 6 mM glutamine, amino acids andpenicillin/streptomycin) and then transferred in 12.5 ml medium into aT75cm² flask and incubated overnight at 37 C., 5% CO₂/air. The day aftertransfection the cells were resuspended in selective medium containing 1mg/ml geneticin and dispensed into 5×96-well plates at 200 μl/well.After 18 days at 37 C. (5% CO₂/air) the colony supernatants werescreened by an ELISA that detects assembled human IgG in order toidentify colonies expressing IgG. Approximately twenty positive colonieswere expanded and adapted to growth in serum-free, selective medium.Duplicate T25cm² flasks were set up. Cells from one flask were frozendown as a stock and cells in the second flask were grown to saturation.The productivity of the saturated cultures was assessed by ELISA. Thehighest producing cell lines were then selected for large-scale antibodyproduction.

[0828] The above procedure is exemplified for the I006D08 anti-BLySantibody constructs. Following electroporation and selection of NSOcells, supernatants from ninety-three wells each containing a singlecolony were screened by ELISA to detect assembled IgG1, antibody.Twenty-seven of the supernatants were identified as containing IgG. Thecolonies from 24 of the positive wells were transferred to 1 mlselective medium in a 24-well plate and allowed to grow for 2 days. The1 ml cultures of cells were then added to 4 ml selective mediumcontaining reduced serum (0.5% FCS) in a T25 cm² flask. When thecultures reached confluency 1 ml cells were diluted in 4 ml selective,serum-free medium in a T25 cm² flask. At confluency this subcultureregime was repeated again. Finally 1 ml cells from the culturecontaining 0.1% FCS was diluted with 9 ml serum-free, selective mediumand divided into 2×T25 cm² to form the saturated and stock cultures. Thestock cultures were frozen down and stored in liquid nitrogen once thecultures were confluent. The saturation culture was grown until theviability of the culture was <10%. Twenty-three out of the 24 coloniesoriginally expanded were successfully adapted to growth in serum-freemedium. The productivity of these serum-free adapted cell lines rangedfrom 0.3 to 17 μg/ml by ELISA quantification of the saturated, 5 mlserum-free cultures. The I006D08-32 cell line produced 17 μg/ml.

[0829] Large-scale IgG Production

[0830] The highest-producing cell lines were revived from frozen stocksand then expanded to 400 ml in selective, serum-free medium in 2 literroller bottles. The cells were grown at 37 C. and rolled at 4 rpm withthe headspace being re-equilibrated with 5% CO₂/air every 2-3 days.Finally the culture was expanded to a 4 liter volume by the addition ofserum-free medium without selection (400 ml per 2 liter roller bottle).The cultures were then grown to saturation.

[0831] This procedure is exemplified by the production of I006D08antibody from the I006D08-32 cell line. The frozen stock of I006D08-32was revived into a T25 cm² containing 5 ml serum-free medium containing1 mg/ml geneticin and grown at 37 C. in 5% CO₂/air incubator. After twodays growth the culture was diluted with 7.5 ml fresh medium andtransferred to a T75 cm² flask. After a further three days in theincubator the cells were transferred to 130 ml selective medium andtransferred to a 2 liter roller bottle. After three days growth thecells were diluted with 500 ml selective medium and split into 2×2 literroller bottles. After another 2 days 100 ml fresh selective medium wasadded to each roller. Finally the next day the culture was expanded to atotal volume of 4 liters with non-selective medium and divided into 10×2liter roller bottles. After three days the medium was supplemented with6 mM glutamine. The cells were grown for 17 days from the finalsubculture into a 4 liter volume. The cells grew up to 3×10⁶ cells/mlbefore viability declined to <0.2×10⁶ cells/ml. At this low viabilitythe culture supernatants were harvested. ELISA analysis indicated thatthe culture supernatant contained 33 μg/ml IgG. Hence, the 4 literculture contained 132 mg IgG.

[0832] IgG Purification

[0833] The purification of the IgG from the fermentation broth isperformed using a combination of conventional techniques commonly usedfor antibody production. Typically the culture harvest is clarified toremove cells and cellular debris prior to starting the purificationscheme. This would normally be achieved using either centrifugation orfiltration of the harvest. Following clarification, the antibody wouldtypically be captured and significantly purified using affinitychromatography on Protein A Sepharose. The antibody is bound to ProteinA Sepharose at basic pH and, following washing of the matrix, is elutedby a reduction of the pH. Further purification of the antibody is thenachieved by gel filtration. As well as removing components withdifferent molecular weights from the antibody this step can also be usedto buffer exchange into the desired final formulation buffer.

[0834] Purification of I006D08 IgG1

[0835] The harvest was clarified by sequential filtration through 0.5 μmand 0.22 μm filters. Clarified harvest was then applied to a column ofrecombinant Protein A Sepharose equilibrated at pH 8.0 and washed withthe equilibration buffer. I006D08 antibody was eluted from the Protein ASepharose by application of a buffer at pH3.5. The collected antibodycontaining eluate was then neutralized to pH 7.4 by the addition of pH8.0 buffer. The neutralized eluate was concentrated by ultrafiltrationusing a 30 KDa cut off membrane. Concentrated material was then purifiedby Sephacryl S300HR gel filtration using phosphate buffered saline asthe mobile phase. The final monomeric IgG1 fraction from the gelfiltration column was then concentrated to the desired formulationconcentration by ultrafiltration using a 30 KDa cut off membrane. Thefinal product was filtered through a 0.22 μm filter.

Example 21

[0836] Antibody Neutralization of Murine Splenocyte Proliferation asMeasured by 3HdT Incorporation

[0837] To determine if an antibody inhibited BLyS mediated B cellproliferation, a splenocyte proliferation assay was performed. Briefly,murine splenocytes were isolated by flushing spleen with complete mediumusing a 25 g needle and 10 ml of complete medium (RPMI 1640 with 10% FBScontaining 100 U/ml penicillin, 100 μg/ml streptomycin, 4 mM glutamine,5×10⁻⁵M P-mercaptoethanol). The cells were passed through a 100 micronnylon filter to remove cell clumps. The cell suspension was thenficolled at 400×g for 25 minutes at room temperature (one 15 ml conicaltube/spleen; 3 ml ficol, 10 ml cell suspension/spleen; Ficol 1083 fromSigma). The recovered cells were washed 3 times in complete medium andcounted. Recovered cells were then diluted to a concentration of3×10⁶/ml in complete medium containing a 3×concentration of SAC(3×=1:33,333 dilution of stock) (Staph. aureus Cowan strain;Calbiochem).

[0838] For each antibody, 50 microliters of antibody dilutions at 30μg/ml, 3.0 μg/ml, and 0.3 μg/ml concentrations were aliquotted intoindividual wells of a 96 well plate in triplicate. Suitable positivecontrols, such as, for example monoclonal antibody 15C10, were alsoused. Medium containing no antibody (and human isotype controls(purchased commercially) when necessary) were used as negative controls.

[0839] BLyS protein was diluted in complete medium to concentrations of300 ng/ml, 90 ng/ml and 30 ng/ml. 50 microliters of each of the BLySdilutions were then added to the antibody dilution series in the plates.The plate containing the antibody and BLyS dilutions are then incubatedfor 30 minutes at 37° C., 5% CO₂, after which 50 microliters of thesplenocyte cell suspension containing SAC was added to all wells. Theplates were then incubated for 72 hours (37° C., 5% CO₂).

[0840] After 72 hours, each well was supplemented with 50 μl of completemedium containing 0.5 μCi of 3H-thymidine (6.7 Ci/mM; Amersham) andcells were incubated for an additional 20-24 hours at (37° C., 5% CO₂).Following incubation cells were harvested using a Tomtec Cell Harvesterand filters counted in a TopCount Scintillation counter (Packard).

Example 22

[0841] Human B Cell Proliferation Assay for In Vitro Screening of BLySAntagonist Molecules

[0842] The bioassay for assessing the effects of putative BLySantagonists was performed in triplicate in 96 well format by mixingequal volumes of BLyS, responder cells, and putative antagonist each ofwhich is prepared as a 3× stock reagent.

[0843] B-lymphocytes were purified from human tonsil by MACS (anti-CD3depletion), washed, and resuspended in complete medium (CM) (RPMI 1640with 10% FBS containing 100 U/ml penicillin, 100 μg/ml streptomycin, 4mM glutamine, 5×10E-5 M beta-mercaptoethanol) at a concentration of3×10e6 cells/mL. Staphylococcus aureus, Cowan I (SAC, CalBiochem) wasadded to cells at 3× concentration (3×=1:33,333 dilution of stock

[0844] Meanwhile, eight serial dilutions (3-fold) of potentialantagonist were prepared in CM such that the diluted antagonists are at3× the final concentrations to be tested in the assay. Antibodies areroutinely tested starting at a final concentration of 10 ug/mL and goingdown to about 1.5 ng/mL.

[0845] Human rBLyS was prepared in CM to 3× concentration (3×=300 ng/mL,30 ng/mL, and 3 ng/mL) in CM. Potential inhibitors were routinely testedat several concentrations of BLyS to avoid false negatives due tounexpectedly low affinity or antagonist concentration.

[0846] Fifty microliters of diluted antagonist and 50 uL of diluted BLySwere added to the putative antagonist dilution series.

[0847] Cells were then incubated for 72 hours (37° C., 5% CO₂) in afully humidified chamber. After 72 hrs., the cells were supplementedwith 0.5 μCi/well 3H-thymidine (6.7 Ci/mmol) and incubated for anadditional 24 hours. Plates were harvested using a Tomtec Cell Harvesterand filters counted in a TopCount Scintillation counter (Packard).

[0848] The entire disclosure of each document cited (including patents,patent applications, journal articles, abstracts, laboratory manuals,books, or other disclosures) in this application is incorporated intheir entireties herein by reference. Further, the sequences disclosedherein are also disclosed in U.S. Provisional Application 60/212,210filed Jun. 16, 2000 the contents of which are incorporated in theirentireties herein by reference. TABLE 1 scFvs that ImmunospecificallyBind to BLyS scFv SEQ ID AAs of AAs of AAs of AAs of AAs of AAs of VHAAs of VH AAs of VH Clone ID NO VL VL CDR1 VL CDR2 VL CDR3 VH CDR1 CDR2CDR3 VH CDR3 Sequence (SEQ ID NO) I003F12S 1 138-248 160-173 22 189-195228-237 1-122 26-35 50-66 99-111 HDDDVLTGYYFES (SEQ ID NO: 2130) I006D082 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYGMDV (SEQ ID NO: 2133) I008A11 3 144-254 166-179 195-201234-243 1-128 26-37 52-69 102-117  DRYDILTGYYYYGMDV (SEQ ID NO: 2129)I017D10 4 148-255 169-179 195-201 234-244 1-132 26-35 50-66 99-121VQMDSEYYDLLTGINVGPYYFDY (SEQ ID NO: 2132) I022D01 5 142-249 163-173189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO:2135) I031F02 6 137-251 160-173 189-195 228-240 1-121 26-35 50-66 99-110GYDSSAFRAFDI (SEQ ID NO: 2136) I050A12 7 140-250 164-174 190-196 229-2391-124 26-35 50-66 99-113 APYDLLTHYFHYFDY (SEQ ID NO: 2134) I051C04 8145-256 168-181 197-203 236-245 1-129 26-35 50-66 99-118AATTSQKHNKYAYYFYGMDV (SEQ ID NO: 2131) I050B11 9 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I050B11-01 10 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQVWVA (SEQ ID NO: 2143) I050B11-02 11 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQVWVA (SEQ ID NO: 2143)I050B11-03 12 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTRYVFQYFDH (SEQ ID NO: 2144) I050B11-04 13 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTGYVFQYFDH (SEQ ID NO: 2141)I050B11-05 14 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTRYVFQVWVA (SEQ ID NO: 2142) I050B11-06 15 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTGYVFQVWVA (SEQ ID NO: 2140)I050B11-07 16 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTRYVFQYFDH (SEQ ID NO: 2144) I050B11-08 17 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTGYVFQYFDH (SEQ ID NO: 2141)I050B11-09 18 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTRYVFQVWVA (SEQ ID NO: 2142) I050B11-10 19 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTRYVFQVWVA (SEQ ID NO: 2142)I050B11-11 20 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTGYVFQVWVA (SEQ ID NO: 2140) I050B11-12 21 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTGYVFQVWVA (SEQ ID NO: 2140)I050B11-13 22 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I050B11-14 23 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I050B11-15 24 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQVWVA (SEQ ID NO: 2143) I050B11-16 25 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQVWVA (SEQ ID NO: 2143)I050B11-17 26 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTRYVFQYFDH (SEQ ID NO: 2144) I050B11-18 27 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTRYVFQYFDH (SEQ ID NO: 2144)I050B11-19 28 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDILTSYVFQYFDH (SEQ ID NO: 2139) I050B11-20 29 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDILTSYVFQYFDH (SEQ ID NO: 2139)I050B11-21 30 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDILTRYVFQYFDH (SEQ ID NO: 2138) I050B11-22 31 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDILTRYVFQYFDH (SEQ ID NO: 2138)I050B11-23 32 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDILTRYVFQYFDH (SEQ ID NO: 2138) I050B11-24 33 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDILTSYVFQYFDH (SEQ ID NO: 2139)I050B11-25 34 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTRYVFQYFDH (SEQ ID NO: 2144) I050B11-26 35 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDILTSYVFQYFDH (SEQ ID NO: 2139)I050B11-27 36 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDILTRYVFQYFDH (SEQ ID NO: 2138) I050B11-28 37 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093D03 38 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLGYYLS (SEQ ID NO: 2145) I093D09 39 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093G08 40 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQVWVA (SEQ ID NO: 2143) I097D11 41 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDILTSYVFQYFDH (SEQ ID NO: 2139)I101A04 42 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I101B01 43 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I102A02 44 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I102E01 45 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTRYVFQYFDH (SEQ ID NO: 2144)I102G06 46 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTGYVFQYFDH (SEQ ID NO: 2141) I087A07 47 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLPRVIP (SEQ ID NO: 2227)I087A08 48 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVCRPHF (SEQ ID NO: 2238) I087A09 49 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVRCPYV (SEQ ID NO: 2272)I087B02 50 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVFRPDL (SEQ ID NO: 2281) I087B03 51 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVKSMPT (SEQ ID NO: 2305)I087B04 52 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVPFLYC (SEQ ID NO: 2292) I087B05 53 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVPVPST (SEQ ID NO: 2270)I087B06 54 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVGIHGL (SEQ ID NO: 2282) I087B08 55 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVPCSPPR (SEQ ID NO: 2261)I087B09 56 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVCYPPA (SEQ ID NO: 2240) I087C02 57 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVLPLLS (SEQ ID NO: 2224)I087C05 58 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVALYRL (SEQ ID NO: 2234) I087C06 59 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVRASFS (SEQ ID NO: 2271)I087C07 60 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVCTPVP (SEQ ID NO: 2319) I087C08 61 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVWPSFFS (SEQ ID NO: 2277)I087D01 62 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVTPRGY (SEQ ID NO: 2275) I087D02 63 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVSSLLS (SEQ ID NO: 2213)I087D03 64 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVPLLPLC (SEQ ID NO: 2263) I087D05 65 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVPPPSFL (SEQ ID NO: 2266)I087D07 66 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVPTSTT (SEQ ID NO: 2269) I087D09 67 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVISCSWA (SEQ ID NO: 2299)I087E04 68 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVSALPPP (SEQ ID NO: 2274) I087E05 69 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVCRHLF (SEQ ID NO: 2236)I087E10 70 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVVSFPSL (SEQ ID NO: 2307) I087F02 71 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVMGVTPS (SEQ ID NO: 2322)I087F04 72 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLFRPVL (SEQ ID NO: 2326) I087F05 73 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVPSVGG (SEQ ID NO: 2267)I087F07 74 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVPPTRH (SEQ ID NO: 2286) I087F08 75 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVLRSRD (SEQ ID NO: 2243)I087F09 76 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVPLLPP (SEQ ID NO: 2310) I087G05 77 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVLRCVL (SEQ ID NO: 2239)I087G06 78 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVHPSRS (SEQ ID NO: 2285) I087G07 79 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLRLPPQ (SEQ ID NO: 2241)I087G09 80 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVGPYGT (SEQ ID NO: 2284) I087G10 81 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVTTPCT (SEQ ID NO: 2276)I087H02 82 137-244 160-170 186-192 225-233 1-121 26-35 50-66 99-110ASYLSTSSSLDN (SEQ ID NO: 2265) I088A01 83 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088A03 84 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVIPFLPL (SEQ ID NO: 2290) I088A04 85 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLHIYPH (SEQ ID NO: 2335)I088A08 86 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTNYVFEYYAS (SEQ ID NO: 2323) I088A09 87 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVILYYLH (SEQ ID NO: 2295)I088A10 88 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088A11 89 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLMYFPH (SEQ ID NO: 2220)I088A12 90 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLFFYPL (SEQ ID NO: 2325) I088B01 91 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088B02 92 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFDYYAS (SEQ ID NO: 2244) I088B03 93 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVIPFLPL (SEQ ID NO: 2290)I088B05 94 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088B06 95 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFEYYSL (SEQ ID NO: 2324)I088B07 96 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088B08 97 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088B09 98 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLEFYLL (SEQ ID NO: 2303) I088B10 99 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088B12 100 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVLPLDS (SEQ ID NO: 2223) I088C01 101 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLYFYPS (SEQ ID NO: 2317)I088C03 102 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088C09 103 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088C12 104 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088D01 105 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088D03 106 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYYAL (SEQ ID NO: 2215) I088D04 107 140-250 165-176 192-198231-239 1-124 26-35 50-66 99-113 PFYDTLTSYVLPPSV (SEQ ID NO: 2225)I088D07 108 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088D08 109 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088D11 110 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088E01 111 138-248 163-174 190-196229-237 1-122 23-32 47-63 96-111 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088E02 112 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYYLY (SEQ ID NO: 2216) I088E03 113 141-251 166-177 193-199232-249 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088E04 114 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088E08 115 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088E10 116 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088E11 117 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088F07 118 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088G02 119 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I088G03 120 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088G07 121 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFHYYPL (SEQ ID NO: 2260)I088G09 122 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFPVYYL (SEQ ID NO: 2264) I088G10 123 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLHFIDH (SEQ ID NO: 2301)I088H05 124 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I088H07 125 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092A03 126 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092A05 127 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFHYYDV (SEQ ID NO: 2258)I092A06 128 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092A08 129 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVHEFFSL (SEQ ID NO: 2283)I092A10 130 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092A11 131 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092B01 132 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092B02 133 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092B04 134 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092B05 135 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092B10 136 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092B12 137 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092C01 138 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092C02 139 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092C07 140 140-250 165-176 192-198 231-239 1-124 26-35 50-66 99-113PFYDTLTSYVLALDL (SEQ ID NO: 2328) I092C08 141 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFGYYSL (SEQ ID NO: 2254)I092C12 142 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092D01 143 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLKYYTD (SEQ ID NO: 2226)I092D07 144 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092D09 145 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVMHAYPL (SEQ ID NO: 2255)I092D10 146 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFHYLPV (SEQ ID NO: 2256) I092D11 147 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092E01 148 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092E03 149 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYAFQYFDH (SEQ ID NO: 2230)I092E04 150 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFEYFSV (SEQ ID NO: 2248) I092E07 151 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092E10 152 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLFYYPL (SEQ ID NO: 2327) I092E11 153 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092F01 154 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092F02 155 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092F05 156 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092F07 157 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092F08 158 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092F11 159 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092F12 160 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLAYYPD (SEQ ID NO: 2306) I092G01 161 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092G05 162 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I092G10 163 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I092H01 164 137-244 160-170 186-192 225-233 1-121 26-35 50-66 99-110ASYLSTSSSLDN (SEQ ID NO: 2265) I093A06 165 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLPVYDH (SEQ ID NO: 2334)I093A09 166 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFAH (SEQ ID NO: 2268) I093A11 167 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093A12 168 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I093B02 169 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093B05 170 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVIFYYPT (SEQ ID NO: 2289) I093B06 171 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093B09 172 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLEVYHP (SEQ ID NO: 2318) I093B12 173 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFAPLVT (SEQ ID NO: 2242)I093C02 174 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHAYAF (SEQ ID NO: 2332) I093C03 175 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093C05 176 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVILYYLH (SEQ ID NO: 2295) I093D05 177 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFEFLPL (SEQ ID NO: 2245)I093D08 178 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVRPFYAH (SEQ ID NO: 2273) I093D10 179 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093D12 180 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHFYRV (SEQ ID NO: 2302) I093E01 181 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093E02 182 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVIQYFDH (SEQ ID NO: 2297) I093E05 183 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVHEFFSL (SEQ ID NO: 2283)I093E08 184 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVMQFFPT (SEQ ID NO: 2321) I093E10 185 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLSFYPV (SEQ ID NO: 2246)I093F01 186 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLYYYAF (SEQ ID NO: 2251) I093F03 187 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093F05 188 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I093F08 189 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093F11 190 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHFYPL (SEQ ID NO: 2333) I093G07 191 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLQYYVL (SEQ ID NO: 2237)I093G11 192 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I093G12 193 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I093H06 194 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I094A08 195 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDY (SEQ ID NO: 2280)I094B07 196 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLPVWVS (SEQ ID NO: 2228) I094B08 197 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I094B12 198 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I094C11 199 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I094C12 200 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I094D06 201 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVIEYYPV (SEQ ID NO: 2288)I094D07 202 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I094D08 203 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLHYLPL (SEQ ID NO: 2314)I094D09 204 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I094D10 205 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I094D11 206 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFHFYPV (SEQ ID NO: 2218) I094E04 207 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I094E08 208 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLEAFSL (SEQ ID NO: 2311) I094F04 209 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFGFYPF (SEQ ID NO: 2252)I094F05 210 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I094F10 211 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PIYDTLTSYVFQYFDH (SEQ ID NO: 2278)I094F11 212 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLWYYQD (SEQ ID NO: 2249) I094F12 213 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVIPFYPL (SEQ ID NO: 2296)I094G06 214 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I094G10 215 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I095A04 216 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I095A12 217 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLEYFPL (SEQ ID NO: 2320)I095B04 218 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLEFFPA (SEQ ID NO: 2312) I095B09 219 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVIEYLPL (SEQ ID NO: 2287)I095B10 220 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYYSA (SEQ ID NO: 2217) I095C02 221 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLFYYTA (SEQ ID NO: 2331)I095C05 222 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYLPV (SEQ ID NO: 2337) I095C07 223 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I095C08 224 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I095C09 225 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVMHYYPT (SEQ ID NO: 2259)I095D01 226 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I095D02 227 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLQYFRY (SEQ ID NO: 2235)I095D03 228 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLQVFDT (SEQ ID NO: 2233) I095D05 229 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I095D09 230 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I095E01 231 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLDYYSS (SEQ ID NO: 2309)I095E05 232 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDALTSYVFQYFDH (SEQ ID NO: 2221) I095E12 233 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I095F06 234 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFPFYPH (SEQ ID NO: 2262) I095F09 235 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVIGFYPV (SEQ ID NO: 2291)I095G06 236 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I095G09 237 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVMDFYSV (SEQ ID NO: 2253)I095G11 238 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I096A01 239 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096A10 240 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLPFYAL (SEQ ID NO: 2222) I096B01 241 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096B03 242 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I096C01 243 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096C06 244 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLPYLTH (SEQ ID NO: 2229) I096C09 245 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096D01 246 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I096D02 247 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096D05 248 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I096D06 249 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096D09 250 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I096E02 251 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLGFYPV (SEQ ID NO: 2329)I096E06 252 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYHTH (SEQ ID NO: 2336) I096E11 253 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096F02 254 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVIHFLPL (SEQ ID NO: 2330) I096G01 255 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVIPFLPL (SEQ ID NO: 2290)I096G02 256 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I096G05 257 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I096G07 258 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I096G09 259 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVMHYLPV (SEQ ID NO: 2257)I096G12 260 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLEFFSH (SEQ ID NO: 2315) I096H01 261 137-244 160-170 186-192225-233 1-121 26-35 50-66 99-110 ASYLSTSSSLDN (SEQ ID NO: 2265) I097A04262 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVIHYLVT (SEQ ID NO: 2294) I097A06 263 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLPYYTL (SEQ ID NO: 2231)I097A09 264 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYYPI (SEQ ID NO: 2298) I097B02 265 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLWFYPL (SEQ ID NO: 2247)I097B09 266 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I097B10 267 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I097B11 268 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I097C05 269 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLHYYTH (SEQ ID NO: 2219)I097C09 270 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYYAY (SEQ ID NO: 2316) I097C11 271 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I097D05 272 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVIHFYSL (SEQ ID NO: 2293) I097D06 273 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFGFFPH (SEQ ID NO: 2300)I097E01 274 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I097E04 275 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I097E08 276 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I097E09 277 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I097F09 278 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I097G10 279 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFAH (SEQ ID NO: 2268)I097H02 280 137-244 160-170 186-192 225-233 1-121 26-35 50-66 99-110ASYLSTSSSLDN (SEQ ID NO: 2265) I098A04 281 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I098A05 282 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I098B08 283 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLDFYSV (SEQ ID NO: 2308)I098C01 284 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PIYDTLTSYVFQYFDH (SEQ ID NO: 2278) I098C04 285 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVLYYYAF (SEQ ID NO: 2251)I098F11 286 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I098F12 287 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFFFYPF (SEQ ID NO: 2250)I098G02 288 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I098G12 289 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I098H05 290 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I101A01 291 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I101B04 292 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I101B06 293 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVIPFLTH (SEQ ID NO: 2304)I101D04 294 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLEFFPD (SEQ ID NO: 2313) I101D07 295 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I101E09 296 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDR (SEQ ID NO: 2279) I101E12 297 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I101G02 298 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I101G11 299 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I102C03 300 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I102E09 301 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I102F02 302 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I102G08 303 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I102G09 304 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVLHYYAH (SEQ ID NO: 2214) I106A09 305 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I106B02 306 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I106B06 307 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I106C07 308 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I106E05 309 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I106E12 310 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I106G01 311 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I106G03 312 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I109B06 313 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I109D12 314 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I109E12 315 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I109G06 316 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I109H04 317 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQ ID NO: 2137)I110B03 318 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I112D09 319 141-251 166-177 193-199232-240 1-125 26-35 50-66 99-114 PFYDTLTSYGFQYFDH (SEQ ID NO: 2232)I112F10 320 141-251 166-177 193-199 232-240 1-125 26-35 50-66 99-114PFYDTLTSYVFQYFDH (SEQ ID NO: 2137) I089F12 321 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHGLDS (SEQ ID NO: 2146)I105E12 322 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I108D08 323 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLAPLYP (SEQ ID NO: 2148)I108E06 324 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHGLDV (SEQ ID NO: 2151) I113E07 325 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSLDL (SEQ ID NO: 2152)I114G05 326 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I116A01 327 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHALSP (SEQ ID NO: 2149)I116A09 328 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRYLLLFPHHSFDL (SEQ ID NO: 2150) I116C11 329 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I085A01 330 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDHLLF (SEQ ID NO: 2602) I085A02 331 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSDPLGF (SEQ ID NO: 2639)I085A03 332 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTHPLSF (SEQ ID NO: 2561) I085A04 333 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLAPLFF (SEQ ID NO: 2550)I085A05 334 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSDPLSL (SEQ ID NO: 2659) I085A06 335 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLSF (SEQ ID NO: 2611)I085A07 336 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPASPLSF (SEQ ID NO: 2390) I085A09 337 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 SRDLLLFPNDALS (SEQ ID NO: 2632) I085A10338 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLRF (SEQ ID NO: 2609) I085A11 339 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 SRDLLLFPHDPLE (SEQ ID NO: 2363) I085B01340 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQSPLYP (SEQ ID NO: 2466) I085B02 341 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSSLVF (SEQ ID NO: 2392)I085B03 342 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYDPLLF (SEQ ID NO: 2638) I085B04 343 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLYF (SEQ ID NO: 2589)I085B05 344 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLSP (SEQ ID NO: 2573) I085B06 345 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLSPLSF (SEQ ID NO: 2574)I085B07 346 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPDFPMAP (SEQ ID NO: 2433) I085B10 347 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 SRDLLLFPHSPLY (SEQ ID NO: 2470) I085B12348 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQDPLSP (SEQ ID NO: 2372) I085C02 349 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDDPLLS (SEQ ID NO: 2430)I085C03 350 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHGPLLI (SEQ ID NO: 2400) I085C05 351 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGSPLLF (SEQ ID NO: 2491)I085C06 352 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTAALSF (SEQ ID NO: 2341) I085C07 353 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHTPLRF (SEQ ID NO: 2375)I085C09 354 138-248 162-172 188-194 227-237 1-122 26-35 50-66 99-111SRDLLLFPHSPLT (SEQ ID NO: 2468) I085C10 355 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPFSPLLF (SEQ ID NO: 2471)I085C12 356 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSHPLFF (SEQ ID NO: 2680) I085D01 357 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRPLLLF (SEQ ID NO: 2548)I085D02 358 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSQYLDF (SEQ ID NO: 2523) I085D03 359 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSSPLLF (SEQ ID NO: 2713)I085D04 360 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYFPLVF (SEQ ID NO: 2646) I085D06 361 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGSPLLD (SEQ ID NO: 2488)I085D07 362 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLLF (SEQ ID NO: 2694) I085D08 363 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSYLSP (SEQ ID NO: 2477)I085D09 364 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQTPLFP (SEQ ID NO: 2467) I085D10 365 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSPLHP (SEQ ID NO: 2563)I085D11 366 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLAP (SEQ ID NO: 2510) I085D12 367 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHTTLRF (SEQ ID NO: 2495)I085E01 368 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYAVLHF (SEQ ID NO: 2620) I085E02 369 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTSPLRL (SEQ ID NO: 2575)I085E07 370 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSDALSF (SEQ ID NO: 2568) I085E08 371 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNAPLDP (SEQ ID NO: 2603)I085E09 372 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPPRF (SEQ ID NO: 2628) I085E10 373 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSEPLWP (SEQ ID NO: 2668)I085E11 374 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLSN (SEQ ID NO: 2716) I085E12 375 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHLPLTP (SEQ ID NO: 2431)I085F01 376 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRSPLLF (SEQ ID NO: 2551) I085F02 377 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTSPLQL (SEQ ID NO: 2376)I085F03 378 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYTPLLF (SEQ ID NO: 2682) I085F04 379 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSSPLAF (SEQ ID NO: 2707)I085F05 380 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPLYF (SEQ ID NO: 2706) I085F06 381 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAHLLF (SEQ ID NO: 2586)I085F07 382 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SPDLLLFPAGPLRF (SEQ ID NO: 2410) I085F09 383 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDHAFFV (SEQ ID NO: 2439)I085F10 384 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSDSGFA (SEQ ID NO: 2662) I085F11 385 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSSYLEF (SEQ ID NO: 2339)I085F12 386 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRDPLII (SEQ ID NO: 2558) I085G01 387 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLHP (SEQ ID NO: 2605)I085G02 388 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNAPLLL (SEQ ID NO: 2613) I085G03 389 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPAAPLLF (SEQ ID NO: 2403)I085G04 390 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLDP (SEQ ID NO: 2601) I085G07 391 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNAVLDI (SEQ ID NO: 2629)I085G08 392 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSEPLFF (SEQ ID NO: 2664) I085G09 393 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSSVLWP (SEQ ID NO: 2338)I085G10 394 138-248 162-172 188-194 227-237 1-122 26-35 50-66 99-111SRDLLLFPHAPLQ (SEQ ID NO: 2554) I085G11 395 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDSPLAP (SEQ ID NO: 2445)I085G12 396 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLHP (SEQ ID NO: 2576) I085H10 397 142-249 163-173 189-195228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135)I086A03 398 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSMPLTF (SEQ ID NO: 2695) I086A04 399 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSILHP (SEQ ID NO: 2438)I086A05 400 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLSH (SEQ ID NO: 2569) I086A07 401 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDAALRF (SEQ ID NO: 2421)I086A09 402 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSHLSF (SEQ ID NO: 2704) I086A10 403 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLSS (SEQ ID NO: 2624)I086A11 404 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLTP (SEQ ID NO: 2577) I086A12 405 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYDPLHS (SEQ ID NO: 2635)I086B02 406 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHFPLHP (SEQ ID NO: 2348) I086B03 407 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPAHPLLF (SEQ ID NO: 2412)I086B05 408 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPFEPLII (SEQ ID NO: 2457) I086B06 409 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPASPLNP (SEQ ID NO: 2364)I086B07 410 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLYF (SEQ ID NO: 2720) I086B09 411 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTSPLSF (SEQ ID NO: 2579)I086B10 412 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPDDGLSS (SEQ ID NO: 2428) I086B11 413 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPISPLCF (SEQ ID NO: 2530)I086C03 414 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTAPLYG (SEQ ID NO: 2535) I086C05 415 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSLFF (SEQ ID NO: 2427)I086C07 416 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQGPLRF (SEQ ID NO: 2440) I086C08 417 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPAAPLAF (SEQ ID NO: 2401)I086C09 418 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHLPLLF (SEQ ID NO: 2350) I086C10 419 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTFPLIF (SEQ ID NO: 2541)I086C11 420 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPDDPLSF (SEQ ID NO: 2432) I086C12 421 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTDSLLF (SEQ ID NO: 2622)I086D01 422 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLTP (SEQ ID NO: 2630) I086D04 423 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRYLLLFPYAPLYD (SEQ ID NO: 2697)I086D05 424 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHSPLSF (SEQ ID NO: 2461) I086D06 425 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLDL (SEQ ID NO: 2379)I086D07 426 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHTHLTF (SEQ ID NO: 2365) I086D08 427 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSSLDF (SEQ ID NO: 2473)I086D09 428 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNHPMFP (SEQ ID NO: 2665) I086D10 429 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLSSLEF (SEQ ID NO: 2587)I086D11 430 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNAPLHP (SEQ ID NO: 2610) I086D12 431 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAHLRF (SEQ ID NO: 2469)I086E02 432 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYDPLHF (SEQ ID NO: 2621) I086E03 433 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHDALQS (SEQ ID NO: 2598)I086E05 434 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRTPLTF (SEQ ID NO: 2567) I086E07 435 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPAAHLSF (SEQ ID NO: 2398)I086E08 436 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLLF (SEQ ID NO: 2490) I086E09 437 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPFSPLAP (SEQ ID NO: 2464)I086E10 438 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLDF (SEQ ID NO: 2367) I086E12 439 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLRF (SEQ ID NO: 2522)I086F02 440 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLRI (SEQ ID NO: 2714) I086F05 441 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTEPLQF (SEQ ID NO: 2540)I086F08 442 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSDPLSA (SEQ ID NO: 2643) I086F09 443 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYNPPIF (SEQ ID NO: 2653)I086F11 444 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHTPLLF (SEQ ID NO: 2489) I086G03 445 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLDL (SEQ ID NO: 2513)I086G04 446 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPFDPLLI (SEQ ID NO: 2454) I086G05 447 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTDALRI (SEQ ID NO: 2537)I086G06 448 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPAAPLTP (SEQ ID NO: 2407) I086G07 449 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPEGPLLF (SEQ ID NO: 2448)I086G09 450 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYAPLSF (SEQ ID NO: 2385) I086G10 451 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPADSLSF (SEQ ID NO: 2391)I086H05 452 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYSPLTH (SEQ ID NO: 2679) I089A01 453 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 SRDLLLFPHDPLI (SEQ ID NO: 2612) I089A03454 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPLTPLLI (SEQ ID NO: 2590) I089A06 455 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHTPLHF (SEQ ID NO: 2485)I089A07 456 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTDALYF (SEQ ID NO: 2539) I089A08 457 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYTPLLF (SEQ ID NO: 2682)I089A10 458 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHQPLTF (SEQ ID NO: 2436) I089A11 459 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRTYLDF (SEQ ID NO: 2572)I089B01 460 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHSPLHS (SEQ ID NO: 2450) I089B02 461 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I089B03 462 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTSPLQP (SEQ ID NO: 2528) I089B04 463 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTHPLLF (SEQ ID NO: 2556)I089B05 464 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLIF (SEQ ID NO: 2712) I089B06 465 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPMAPLSP (SEQ ID NO: 2596)I089B07 466 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYSGLDA (SEQ ID NO: 2374) I089B08 467 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPAAPLSP (SEQ ID NO: 2405)I089B09 468 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPKSPILF (SEQ ID NO: 2384) I089B10 469 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTSPLFF (SEQ ID NO: 2571)I089B11 470 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNSPLFP (SEQ ID NO: 2388) I089C01 471 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYGMDV (SEQ ID NO: 2133)I089C02 472 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRSPLLF (SEQ ID NO: 2551) I089C03 473 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYHPLLF (SEQ ID NO: 2532)I089C05 474 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSALRF (SEQ ID NO: 2722) I089C06 475 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSPYLSF (SEQ ID NO: 2701)I089C07 476 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLFD (SEQ ID NO: 2683) I089C09 477 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPFTF (SEQ ID NO: 2507)I089D01 478 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLVL (SEQ ID NO: 2581) I089D02 479 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYGMDV (SEQ ID NO: 2133)I089D03 480 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I089D04 481 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSSPLSP (SEQ ID NO: 2717)I089D05 482 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLFT (SEQ ID NO: 2546) I089D07 483 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNDPLLI (SEQ ID NO: 2634)I089D08 484 138-248 162-172 188-194 227-237 1-122 26-35 50-66 99-111SRDLLLFPHAPLQ (SEQ ID NO: 2554) I089D09 485 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSHAFHE (SEQ ID NO: 2677)I089D11 486 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNHPLYP (SEQ ID NO: 2663) I089E01 487 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYSPLFP (SEQ ID NO: 2657)I089E02 488 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQDPLHP (SEQ ID NO: 2346) I089E03 489 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDAPLFP (SEQ ID NO: 2423)I089E04 490 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHSPLLI (SEQ ID NO: 2453) I089E06 491 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGSPLLF (SEQ ID NO: 2491)I089E09 492 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLTF (SEQ ID NO: 2718) I089E10 493 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTQPLSF (SEQ ID NO: 2566)I089E11 494 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPLSPLWP (SEQ ID NO: 2578) I089F01 495 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTFPLLF (SEQ ID NO: 2380)I089F03 496 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPLLL (SEQ ID NO: 2580) I089F04 497 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYSPLLF (SEQ ID NO: 2670)I089F05 498 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHSPLRI (SEQ ID NO: 2459) I089F06 499 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAPLLF (SEQ ID NO: 2490)I089F08 500 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRTPLTF (SEQ ID NO: 2567) I089F09 501 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLAPLSF (SEQ ID NO: 2555)I089F10 502 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNQPLSF (SEQ ID NO: 2667) I089F11 503 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLEPMHF (SEQ ID NO: 2565)I089G01 504 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLTF (SEQ ID NO: 2626) I089G02 505 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSHPLLF (SEQ ID NO: 2687)I089G03 506 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRTPLVF (SEQ ID NO: 2721) I089G05 507 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGSPLTF (SEQ ID NO: 2389)I089G06 508 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTAPLLF (SEQ ID NO: 2514) I089G07 509 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLDF (SEQ ID NO: 2597)I089G08 510 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSHPLSF (SEQ ID NO: 2688) I089G11 511 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSFPLLF (SEQ ID NO: 2671)I089H10 512 142-249 163-173 189-195 228-238 1-126 26-35 50-66 99-115DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I090A02 513 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPAKPLLF (SEQ ID NO: 2416)I090A03 514 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNSTLSF (SEQ ID NO: 2678) I090A04 515 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDAPLTP (SEQ ID NO: 2426)I090A05 516 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHEPLLI (SEQ ID NO: 2648) I090A06 517 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTYPLSF (SEQ ID NO: 2600)I090A07 518 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTEPLVL (SEQ ID NO: 2479) I090A08 519 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTYPLHF (SEQ ID NO: 2584)I090B01 520 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPLTF (SEQ ID NO: 2627) I090B03 521 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLTN (SEQ ID NO: 2705)I090B04 522 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLEA (SEQ ID NO: 2520) I090B05 523 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDHPLLF (SEQ ID NO: 2442)I090B06 524 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLSF (SEQ ID NO: 2496) I090B08 525 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRGPLRF (SEQ ID NO: 2542)I090B11 526 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPFTPLTF (SEQ ID NO: 2474) I090B12 527 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQHPLSP (SEQ ID NO: 2452)I090C01 528 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPIVF (SEQ ID NO: 2591) I090C02 529 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLTF (SEQ ID NO: 2702)I090C03 530 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLRF (SEQ ID NO: 2493) I090C05 531 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRTPLTF (SEQ ID NO: 2567)I090C06 532 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLDF (SEQ ID NO: 2538) I090C07 533 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAGFDS (SEQ ID NO: 2498)I090C08 534 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYSPLSF (SEQ ID NO: 2676) I090C10 535 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGRPLTF (SEQ ID NO: 2358)I090D02 536 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPAEHLLF (SEQ ID NO: 2408) I090D03 537 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLHP (SEQ ID NO: 2351)I090D04 538 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHEPLTA (SEQ ID NO: 2654) I090D05 539 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLFE (SEQ ID NO: 2529)I090D06 540 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLDF (SEQ ID NO: 2367) I090D07 541 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPFGTLRF (SEQ ID NO: 2462)I090D08 542 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLVF (SEQ ID NO: 2723) I090D09 543 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLAF (SEQ ID NO: 2505)I090D12 544 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTSPLSF (SEQ ID NO: 2579) I090E04 545 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLLL (SEQ ID NO: 2552)I090E05 546 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPISF (SEQ ID NO: 2588) I090E06 547 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQGPLSF (SEQ ID NO: 2443)I090E07 548 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPGSPLHP (SEQ ID NO: 2484) I090E09 549 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSDPLSF (SEQ ID NO: 2647)I090E11 550 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDGLAP (SEQ ID NO: 2700) I090E12 551 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTSPLTF (SEQ ID NO: 2582)I090F01 552 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNGPLHP (SEQ ID NO: 2649) I090F02 553 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLSF (SEQ ID NO: 2696)I090F03 554 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTAPLSF (SEQ ID NO: 2526) I090F04 555 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPFFPLQF (SEQ ID NO: 2460)I090F05 556 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPLDPLHF (SEQ ID NO: 2359) I090F06 557 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSEPLQL (SEQ ID NO: 2666)I090F07 558 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPFAPLRF (SEQ ID NO: 2451) I090F08 559 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLHPLIF (SEQ ID NO: 2570)I090F09 560 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I090F10 561 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLRI (SEQ ID NO: 2527)I090F11 562 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSNPLTF (SEQ ID NO: 2698) I090G01 563 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLEI (SEQ ID NO: 2347)I090G02 564 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRDPLQF (SEQ ID NO: 2395) I090G04 565 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHEPLAF (SEQ ID NO: 2633)I090G05 566 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLAF (SEQ ID NO: 2472) I090G06 567 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYSPLAF (SEQ ID NO: 2656)I090G07 568 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHTPLDS (SEQ ID NO: 2480) I090G08 569 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHTPLTF (SEQ ID NO: 2492)I090G09 570 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSEPLRI (SEQ ID NO: 2356) I090G10 571 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLDF (SEQ ID NO: 2343)I090G12 572 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNRGLDL (SEQ ID NO: 2669) I091A02 573 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYDPLFM (SEQ ID NO: 2724)I091A03 574 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLYP (SEQ ID NO: 2592) I091A06 575 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLAF (SEQ ID NO: 2594)I091A11 576 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHSPITF (SEQ ID NO: 2441) I091B01 577 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRYPLFF (SEQ ID NO: 2585)I091B02 578 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYAPLDF (SEQ ID NO: 2361) I091B04 579 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLQF (SEQ ID NO: 2395)I091B05 580 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLEL (SEQ ID NO: 2475) I091B07 581 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLTF (SEQ ID NO: 2626)I091B10 582 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTAPLAF (SEQ ID NO: 2342) I091B11 583 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSPLDF (SEQ ID NO: 2444)I091B12 584 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSHPLTF (SEQ ID NO: 2690) I091C02 585 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPAHPLVI (SEQ ID NO: 2414)I091C03 586 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLYP (SEQ ID NO: 2378) I091C04 587 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLTF (SEQ ID NO: 2531)I091C05 588 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTTPLHF (SEQ ID NO: 2583) I091C06 589 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPLLF (SEQ ID NO: 2344)I091C09 590 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHPLSF (SEQ ID NO: 2415) I091C11 591 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYHSYDI (SEQ ID NO: 2650)I091C12 592 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYATLSF (SEQ ID NO: 2618) I091D01 593 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNSPLAP (SEQ ID NO: 2672)I091D02 594 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYSPLQP (SEQ ID NO: 2673) I091D04 595 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQGPLSF (SEQ ID NO: 2443)I091D05 596 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPLAP (SEQ ID NO: 2606) I091D06 597 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 SRDLLLFPHSPLL (SEQ ID NO: 2456) I091D07598 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNGALRF (SEQ ID NO: 2645) I091D09 599 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYSPLRF (SEQ ID NO: 2719)I091E01 600 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPDAPLHP (SEQ ID NO: 2425) I091E02 601 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLFP (SEQ ID NO: 2689)I091E03 602 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLWP (SEQ ID NO: 2352) I091E04 603 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPKSPLAF (SEQ ID NO: 2547)I091E06 604 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLHP (SEQ ID NO: 2576) I091E07 605 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNHPLTF (SEQ ID NO: 2661)I091E08 606 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNAPLDS (SEQ ID NO: 2607) I091E09 607 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYAPLDF (SEQ ID NO: 2361)I091E10 608 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSSPLEF (SEQ ID NO: 2711) I091F01 609 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAPLFF (SEQ ID NO: 2486)I091F03 610 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPMAPLVG (SEQ ID NO: 2599) I091F05 611 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLAPLHP (SEQ ID NO: 2553)I091F06 612 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPLGF (SEQ ID NO: 2353) I091F07 613 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYGMDV (SEQ ID NO: 2133)I091F08 614 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQSPLLF (SEQ ID NO: 2458) I091F09 615 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHEHLSF (SEQ ID NO: 2354)I091F10 616 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHSPLDF (SEQ ID NO: 2444) I091F11 617 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSPLSP (SEQ ID NO: 2549)I091F12 618 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYGMDV (SEQ ID NO: 2133) I091G01 619 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNAALYP (SEQ ID NO: 2386)I091G03 620 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNDPLFG (SEQ ID NO: 2355) I091G04 621 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGAPLSP (SEQ ID NO: 2478)I091G05 622 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112ARDLLLFPAAPLWP (SEQ ID NO: 2397) I091G06 623 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 SRDLLLFPNDPLR (SEQ ID NO: 2637) I091G07624 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPTAPLDP (SEQ ID NO: 2345) I091G09 625 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLFP (SEQ ID NO: 2349)I091G10 626 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSDPLVF (SEQ ID NO: 2660) I091G11 627 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGSPLTF (SEQ ID NO: 2389)I091G12 628 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYSHLEF (SEQ ID NO: 2655) I104A01 629 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQSPLHP (SEQ ID NO: 2455)I104A07 630 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLFP (SEQ ID NO: 2689) I104A08 631 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYAPLTF (SEQ ID NO: 2617)I104A09 632 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQNPLHP (SEQ ID NO: 2506) I104A10 633 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHEPLCF (SEQ ID NO: 2636)I104A11 634 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLSF (SEQ ID NO: 2611) I104A12 635 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPMAPLRF (SEQ ID NO: 2593)I104B02 636 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRSPLSF (SEQ ID NO: 2557) I104B04 637 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLYP (SEQ ID NO: 2387)I104B09 638 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRDPLQF (SEQ ID NO: 2395) I104B11 639 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLTF (SEQ ID NO: 2531)I104C01 640 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYSPLYP (SEQ ID NO: 2710) I104C04 641 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPASPLIF (SEQ ID NO: 2417)I104C05 642 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRHPLLF (SEQ ID NO: 2543) I104C06 643 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 SRDLLLFPHAPLE (SEQ ID NO: 2524) I104C07644 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLHP (SEQ ID NO: 2370) I104C09 645 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHFPLIF (SEQ ID NO: 2399)I104C11 646 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHEPLIF (SEQ ID NO: 2644) I104D01 647 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNHAFDL (SEQ ID NO: 2652)I104D02 648 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHTILYP (SEQ ID NO: 2497) I104D03 649 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDWPLYP (SEQ ID NO: 2483)I104D04 650 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLFL (SEQ ID NO: 2511) I104D07 651 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLHP (SEQ ID NO: 2691)I104D08 652 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPMDP (SEQ ID NO: 2595) I104D09 653 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAPLTF (SEQ ID NO: 2500)I104E01 654 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRATLEF (SEQ ID NO: 2502) I104E02 655 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHSPLFP (SEQ ID NO: 2447)I104E03 656 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNDPLVL (SEQ ID NO: 2641) I104E05 657 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHDPLYI (SEQ ID NO: 2463)I104E11 658 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYAPLSF (SEQ ID NO: 2385) I104E12 659 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPASPLNP (SEQ ID NO: 2364)I104F02 660 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPLSP (SEQ ID NO: 2616) I104F03 661 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLRF (SEQ ID NO: 2360)I104F04 662 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPGDPLDF (SEQ ID NO: 2481) I104F05 663 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHGPLTF (SEQ ID NO: 2402)I104F06 664 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLSP (SEQ ID NO: 2573) I104F07 665 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSSPLIL (SEQ ID NO: 2465)I104F10 666 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNSPLSP (SEQ ID NO: 2362) I104F11 667 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQDPLVF (SEQ ID NO: 2708)I104F12 668 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPKAPLVF (SEQ ID NO: 2544) I104G04 669 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLRF (SEQ ID NO: 2559)I104G05 670 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLAP (SEQ ID NO: 2476) I104G09 671 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTAPLNF (SEQ ID NO: 2518)I104G11 672 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRHLLLFPQGPLSF (SEQ ID NO: 2482) I105A02 673 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHLPLNP (SEQ ID NO: 2494)I105A03 674 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I105A04 675 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPGAPLAP (SEQ ID NO: 2487)I105A08 676 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLYP (SEQ ID NO: 2378) I105A09 677 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRSPLSF (SEQ ID NO: 2557)I105A11 678 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSHSFDI (SEQ ID NO: 2692) I105B04 679 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPYSPLHP (SEQ ID NO: 2658)I105B05 680 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYSPLSF (SEQ ID NO: 2676) I105B07 681 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I105B08 682 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I105B10 683 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPASPLNP (SEQ ID NO: 2364)I105B11 684 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHEPLSP (SEQ ID NO: 2651) I105B12 685 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPLDPLII (SEQ ID NO: 2560)I105C02 686 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLAF (SEQ ID NO: 2472) I105C03 687 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSSPLSF (SEQ ID NO: 2715)I105C05 688 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYGMDV (SEQ ID NO: 2133) I105C06 689 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAPLDF (SEQ ID NO: 2367)I105C08 690 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRSPLTF (SEQ ID NO: 2562) I105C12 691 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQHGFDA (SEQ ID NO: 2446)I105D04 692 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRDPLRF (SEQ ID NO: 2360) I105D06 693 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLSF (SEQ ID NO: 2368)I105D08 694 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYAPLAF (SEQ ID NO: 2608) I105D09 695 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAAFDV (SEQ ID NO: 2619)I105D10 696 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHEPLFP (SEQ ID NO: 2640) I105D11 697 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRSALTF (SEQ ID NO: 2519)I105E01 698 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDS (SEQ ID NO: 2422) I105E06 699 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYGMDV (SEQ ID NO: 2133)I105E11 700 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNSPLHP (SEQ ID NO: 2675) I105F03 701 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHPLDS (SEQ ID NO: 2409)I105F06 702 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLHP (SEQ ID NO: 2691) I105F07 703 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSWPLTF (SEQ ID NO: 2340)I105F09 704 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I105F12 705 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPTYPLVF (SEQ ID NO: 2604)I105G03 706 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLHP (SEQ ID NO: 2370) I105G08 707 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPKHPLVF (SEQ ID NO: 2366)I105G09 708 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPASPLNP (SEQ ID NO: 2364) I105G10 709 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDA (SEQ ID NO: 2419)I105G11 710 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDPLLF (SEQ ID NO: 2614) I107A01 711 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRHPLVF (SEQ ID NO: 2545)I107A03 712 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLYP (SEQ ID NO: 2501) I107A06 713 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLDP (SEQ ID NO: 2369)I107A07 714 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNAPLSP (SEQ ID NO: 2371) I107A09 715 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLSP (SEQ ID NO: 2699)I107A12 716 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLSF (SEQ ID NO: 2564) I107B02 717 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLFP (SEQ ID NO: 2533)I107B04 718 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPASPLTF (SEQ ID NO: 2420) I107B05 719 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYGMDV (SEQ ID NO: 2133)I107C01 720 137-247 161-171 187-193 226-236 1-121 24-33 48-64 97-110SRDLLLFPHYPLLF (SEQ ID NO: 2344) I107C02 721 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYGMYV (SEQ ID NO: 2504)I107C04 722 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLHP (SEQ ID NO: 2357) I107C06 723 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLAP (SEQ ID NO: 2510)I107C08 724 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLEP (SEQ ID NO: 2681) I107C10 725 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSHAFDL (SEQ ID NO: 2674)I107D01 726 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYAPLDF (SEQ ID NO: 2361) I107D04 727 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNAPLSF (SEQ ID NO: 2625)I107D07 728 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSHSFDV (SEQ ID NO: 2693) I107D12 729 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDT (SEQ ID NO: 2424)I107E01 730 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPMLGLDL (SEQ ID NO: 2499) I107E05 731 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAPLDF (SEQ ID NO: 2367)I107E07 732 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRSPLLF (SEQ ID NO: 2551) I107E09 733 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPKAPLTF (SEQ ID NO: 2382)I107F01 734 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLSP (SEQ ID NO: 2623) I107F05 735 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLAP (SEQ ID NO: 2510)I107F09 736 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPSAPLAP (SEQ ID NO: 2394) I107F10 737 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRTPLLF (SEQ ID NO: 2373)I107G01 738 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNAPLSP (SEQ ID NO: 2371) I107G05 739 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLYP (SEQ ID NO: 2387)I107H02 740 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I107H06 741 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAPLSF (SEQ ID NO: 2496)I107H09 742 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLEM (SEQ ID NO: 2536) I107H10 743 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLAP (SEQ ID NO: 2510)I108A12 744 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I108B03 745 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLLF (SEQ ID NO: 2515)I108B04 746 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPLSPLVP (SEQ ID NO: 2396) I108C09 747 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHDPLGF (SEQ ID NO: 2353)I108C11 748 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSLLF (SEQ ID NO: 2429) I108D10 749 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPASPLNP (SEQ ID NO: 2364)I108D11 750 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPASPLNP (SEQ ID NO: 2364) I108D12 751 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLNP (SEQ ID NO: 2709)I108E01 752 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I108E03 753 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPKHPLRF (SEQ ID NO: 2393)I108E05 754 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHAPLFP (SEQ ID NO: 2533) I108E07 755 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHAPLDP (SEQ ID NO: 2369)I108E08 756 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I108E09 757 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLSP (SEQ ID NO: 2623)I108E10 758 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRDPLDL (SEQ ID NO: 2509) I108E11 759 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLEF (SEQ ID NO: 2516)I108F10 760 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPNAPLSP (SEQ ID NO: 2371) I108F12 761 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPFDA (SEQ ID NO: 2508)I108G01 762 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRDPLRF (SEQ ID NO: 2360) I108G02 763 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPDAPLAP (SEQ ID NO: 2381)I108G07 764 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLAP (SEQ ID NO: 2476) I108G10 765 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSLLF (SEQ ID NO: 2429)I108G11 766 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHPLTF (SEQ ID NO: 2377) I108G12 767 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHPLTF (SEQ ID NO: 2377)I108H01 768 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRDPLHF (SEQ ID NO: 2512) I108H02 769 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPNAPLNP (SEQ ID NO: 2615)I108H06 770 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I108H08 771 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPASPLNP (SEQ ID NO: 2364)I111A06 772 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQAPLHP (SEQ ID NO: 2691) I111B12 773 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I111C01 774 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQHGLDL (SEQ ID NO: 2449) I111D06 775 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRDPLLF (SEQ ID NO: 2515)I111E04 776 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I111E10 777 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLHP (SEQ ID NO: 2691)I111E11 778 139-250 163-173 189-195 229-239 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I111E12 779 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRYLLLFPHHSFDL (SEQ ID NO: 2150)I111F07 780 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPRAPLYP (SEQ ID NO: 2501) I111G02 781 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPKAPLDF (SEQ ID NO: 2534)I111H10 782 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRYLLLFPQHGFDA (SEQ ID NO: 2703) I113A04 783 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPSAPLWP (SEQ ID NO: 2352)I113A12 784 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQEPLAP (SEQ ID NO: 2434) I113B06 785 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHPLEP (SEQ ID NO: 2411)I113C06 786 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHGFDA (SEQ ID NO: 2406) I113G04 787 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPLLF (SEQ ID NO: 2344)I113G05 788 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYSLLL (SEQ ID NO: 2517) I113G10 789 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHPLQF (SEQ ID NO: 2413)I113G11 790 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I113H06 791 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPLLF (SEQ ID NO: 2344)I113H07 792 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I113H09 793 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYTLLF (SEQ ID NO: 2525)I114C04 794 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHGFDA (SEQ ID NO: 2406) I114C12 795 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLHP (SEQ ID NO: 2691)I114D04 796 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYGMDV (SEQ ID NO: 2133) I114D06 797 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I114D10 798 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYSLVL (SEQ ID NO: 2521) I114E01 799 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQEPLSP (SEQ ID NO: 2435)I114E02 800 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPQESFSL (SEQ ID NO: 2437) I114E03 801 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPKAPLTF (SEQ ID NO: 2382)I114E11 802 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDSFFL (SEQ ID NO: 2383) I114H01 803 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I114H06 804 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHALDV (SEQ ID NO: 2404) I114H09 805 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I115A02 806 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRYLLLFPDHSFDL (SEQ ID NO: 2684) I115A07 807 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPLLF (SEQ ID NO: 2344)I115B10 808 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I115C05 809 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPRAPLYP (SEQ ID NO: 2501)I115C06 810 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRYLLLFPHHSFDL (SEQ ID NO: 2150) I115C08 811 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I115C12 812 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDT (SEQ ID NO: 2424) I115D07 813 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPLLF (SEQ ID NO: 2344)I115E09 814 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHRFDL (SEQ ID NO: 2418) I115F06 815 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRYLLLFPHYGMDV (SEQ ID NO: 2685)I115F07 816 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRYLLLFPHYPLLF (SEQ ID NO: 2686) I115F12 817 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRYLLLFPHHSFDL (SEQ ID NO: 2150)I115G04 818 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHRFDL (SEQ ID NO: 2418) I115G05 819 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPLLF (SEQ ID NO: 2344)I115G08 820 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHDSFDL (SEQ ID NO: 2631) I115H04 821 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHANLSP (SEQ ID NO: 2503)I115H07 822 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I115H09 823 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHRFDL (SEQ ID NO: 2418)I116A07 824 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPYEPLRF (SEQ ID NO: 2642) I116B01 825 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHSFDL (SEQ ID NO: 2147)I116B12 826 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I116C06 827 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHYPLLF (SEQ ID NO: 2344)I116D07 828 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I116E02 829 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPHHRFDL (SEQ ID NO: 2418)I116E04 830 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHHSFDL (SEQ ID NO: 2147) I116F02 831 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRYLLLFPHHSFDL (SEQ ID NO: 2150)I116F11 832 139-249 163-173 189-195 228-238 1-123 26-35 50-66 99-112SRDLLLFPHYPLLF (SEQ ID NO: 2344) I116G05 833 139-249 163-173 189-195228-238 1-123 26-35 50-66 99-112 SRDLLLFPQAPLSP (SEQ ID NO: 2699)I001C09 834 143-250 164-174 190-196 229-239 1-127 26-35 50-66 99-116DGSYDILTGYYIDNYMDV (SEQ ID NO: 2154) I006D07 835 141-248 162-172 188-194227-237 1-125 26-35 50-66 99-114 SHYDILTGLNYWYFDL (SEQ ID NO: 2166)I007B03 836 143-253 165-178 194-200 233-242 1-127 26-35 50-66 99-116DGSYDILTGYYIDNYMDV (SEQ ID NO: 2154) I007F11 837 140-250 162-175 191-197230-239 1-124 26-35 50-66 99-113 DGIDILLVPAALMDV (SEQ ID NO: 2160)I007H08 838 144-254 166-179 195-201 234-243 1-128 26-37 52-69 102-117DRYDILTGYYYYGMDV (SEQ ID NO: 2129) I008A09 839 146-256 168-181 197-203236-245 1-130 26-35 50-66 99-119 DREAYYDILTGYYLYYYYMDV (SEQ ID NO: 2172)I008B01 840 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008C02 841 145-255 167-180 196-202235-244 1-129 26-37 52-67 100-118  HVRDYDILTGYYRGHYFDY (SEQ ID NO: 2167)I008C03 842 143-250 164-174 190-196 229-239 1-127 26-35 50-65 98-116EGSYDILTGYYVGVGRMDV (SEQ ID NO: 2171) I008C12 843 146-256 168-181197-203 236-245 1-130 26-35 50-68 101-119  FNPTYDILTGYYIGGYFQH (SEQ IDNO: 2155) I012A06 844 145-254 169-179 195-201 234-243 1-129 26-37 52-67100-118  GRWDYDLLTGEHLGYYFDY (SEQ ID NO: 2162) I016E05 845 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I016F02 846 135-245 157-170 186-192 225-234 1-119 26-3550-66 99-108 GMGDHYGMDV (SEQ ID NO: 2161) I016F04 847 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I016H07 848 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 GYHDPLTSYNYNWFDP (SEQ ID NO: 2163) I018C02 849 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I018C10 850 143-250 164-174 190-196 229-239 1-127 26-35 50-6699-116 DGSYDILTGYYIDNYMDV (SEQ ID NO: 2154) I018D07 851 143-250 164-174190-196 229-239 1-127 26-35 50-66 99-116 DGSYDILTGYYIDNYMDV (SEQ ID NO:2154) I018H08 852 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I018H09 853 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I021B05 854 143-253 165-178 194-200 233-242 1-127 24-33 48-6497-116 EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I022E02 855 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGLDI (SEQID NO: 2157) I026E03 856 141-251 165-175 191-197 230-240 1-125 26-3550-66 99-114 TDYDILTGYPMGYFDP (SEQ ID NO: 2173) I027A07 857 144-255167-179 195-201 234-244 1-128 26-35 50-66 99-117 GGEYDILTGYYFGLGVYDY(SEQ ID NO: 2170) I028A06 858 142-253 164-176 192-198 231-242 1-12626-35 50-66 99-115 GGDYDILTGLYYYGMDV (SEQ ID NO: 2156) I029D07 859141-250 163-176 192-198 231-239 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I029F11 860 143-253 165-177 193-199232-242 1-127 26-35 50-66 99-116 DGSYDILTGYYIDNYMDV (SEQ ID NO: 2154)I031C03 861 137-248 160-172 188-194 227-237 1-121 26-35 50-66 99-110GYDSSAFRAFDI (SEQ ID NO: 2136) I031C07 862 147-258 170-183 199-205238-247 1-131 26-35 50-66 99-120 SSPPRWYDALTGDSSYHSAMDV (SEQ ID NO:2169) I031F09 863 143-255 167-179 195-201 234-244 1-127 26-35 50-6699-116 DEGRDLLTGYYWPNFFDS (SEQ ID NO: 2168) I031G08 864 147-259 170-182198-204 237-248 1-131 26-35 50-66 99-120 SSPPKWYDALTGHSSYHSAMDV (SEQ IDNO: 2159) I031G10 865 147-258 170-182 198-204 237-247 1-131 26-35 50-6699-120 SSPPKWYDALTGDSSYHSAMDV (SEQ ID NO: 2165) I031G11 866 143-255167-179 195-201 234-244 1-127 26-35 50-66 99-116 DEGRDLLTGYYWPNFFDS (SEQID NO: 2168) I037E07 867 140-250 162-175 191-197 230-239 1-124 26-3550-66 99-113 DGIDILLVPAALMDV (SEQ ID NO: 2160) I037E12 868 140-250162-175 191-197 230-239 1-124 26-35 50-66 99-113 DGIDILLVPAALMDV (SEQ IDNO: 2160) I050A07 869 145-257 168-181 197-203 236-246 1-129 26-40 55-71104-118  QDNDPLTGYKLGFDY (SEQ ID NO: 2164) I061D02 870 144-254 166-179195-201 234-243 1-128 26-37 52-69 102-117  DRYDILTGYYYYGMDV (SEQ ID NO:2129) I061E07 871 141-251 163-175 191-197 230-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I061H01 872 146-256 168-181197-203 236-245 1-130 26-35 50-68 101-119  FNPTYDILTGYYIGGYFQH (SEQ IDNO: 2155) I001A03 873 144-254 166-179 195-201 234-243 1-128 26-35 50-6699-117 ERHYYDILTGYQTGYGMDV (SEQ ID NO: 2784) I001A07 874 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I001A08 875 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I001A10 876 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I001A12 877 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I001B02 878 137-247 159-171187-193 226-236 1-121 26-35 50-66 99-110 DRETKVGYGMDV (SEQ ID NO: 2945)I001B07 879 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I001C06 880 143-253 165-178 194-200233-242 1-127 24-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158)I001C08 881 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117EGSYDILTGYYVGVGRMDV (SEQ ID NO: 2171) I001C12 882 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I001D08 883 140-250 162-175 191-197 230-239 1-124 26-35 50-6598-113 DSYDILTGYRGYYFDY (SEQ ID NO: 2745) I001D12 884 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I001E05 885 143-253 165-178 194-200 233-242 1-127 24-33 48-6497-116 EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I001E07 886 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I001G09 887 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I001H05 888 144-254166-179 195-201 234-243 1-128 26-35 50-66 99-117 ERHYYDILTGYQTGYGMDV(SEQ ID NO: 2784) I001H08 889 141-251 163-176 192-198 231-240 1-12526-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I003A01 890140-251 163-176 192-198 231-240 1-124 26-34 49-65 98-113ELGSSIVGATTGALDM (SEQ ID NO: 2852) I003A06 891 140-251 163-176 192-198231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852)I003A07 892 142-249 163-173 189-195 228-238 1-126 26-35 50-66 99-115DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I003A10 893 141-248 162-172 188-194227-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179)I003B03 894 140-251 163-176 192-198 231-240 1-124 26-34 49-65 98-113ELGSSIVGATTGALDM (SEQ ID NO: 2852) I003B04 895 138-248 162-172 188-194227-237 1-122 25-34 49-65 98-111 RYGDPFYYYYYMNV (SEQ ID NO: 2755)I003B09 896 142-249 163-173 189-195 228-238 1-126 26-35 50-66 99-115DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I003C01 897 140-252 164-176 192-198231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I003C02 898 141-252 164-176 192-198 231-241 1-125 26-35 50-66 99-114GDYDILTGYPAECFQI (SEQ ID NO: 2854) I003C03 899 141-250 164-174 190-196229-239 1-125 26-35 50-66 99-114 GDYDILTGYPAECFQI (SEQ ID NO: 2854)I003C12 900 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I003D04 901 139-250 162-174 190-196229-239 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755)I003E05 902 141-253 164-176 192-198 231-242 1-125 26-35 50-66 99-114GDYDILTGYPAECFQI (SEQ ID NO: 2854) I003F01 903 140-251 163-176 192-198231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852)I003F02 904 139-251 162-175 191-197 230-240 1-123 26-35 50-66 99-112RYGDPFYYYYYMNV (SEQ ID NO: 2755) I003G01 905 143-254 168-179 195-201234-243 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800)I003G05 906 143-255 166-179 195-201 234-244 1-127 26-35 50-66 99-116GSGYDLLTGYFTGSPLDY (SEQ ID NO: 2766) I003G06 907 145-256 168-181 197-203236-245 1-129 26-35 50-66 99-118 DRGGNYDILTGYYFHHGVDV (SEQ ID NO: 2914)I003G11 908 144-251 165-175 191-197 230-240 1-128 26-35 50-66 99-117DAQSYYDILTGYQSYAFDI (SEQ ID NO: 2183) I003H02 909 140-253 164-176192-198 233-242 1-124 26-35 50-66 99-113 DNYDILTGYSRRFDP (SEQ ID NO:2942) I003H05 910 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I003H08 911 142-249 163-173189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO:2135) I005A01 912 141-249 162-172 188-194 227-238 1-125 26-35 50-6699-114 SHYDILTGLNYWYFDL (SEQ ID NO: 2166) I005A02 913 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 EGRDILTGVYYYGLDV (SEQ ID NO:2893) I005B01 914 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 SHYDILTGLNYWYFDL (SEQ ID NO: 2166) I005B09 915 137-247 159-172188-194 227-236 1-121 26-35 50-65 98-110 TYYDILTGRFFDI (SEQ ID NO: 2866)I005C01 916 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114SHYDILTGLNYWYFDL (SEQ ID NO: 2166) I005D02 917 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 DLRYDILTGYHDAFDI (SEQ ID NO: 2890)I005D03 918 142-249 165-175 191-197 230-238 1-126 26-35 50-66 99-115GAYYDILTGYYPYGMDV (SEQ ID NO: 2860) I005E01 919 142-249 165-175 191-197230-238 1-126 26-35 50-66 99-115 GTYYDILTGYFHYGMDV (SEQ ID NO: 2774)I005E08 920 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114SHYDILTGLNYWYFDL (SEQ ID NO: 2166) I005F01 921 140-248 164-174 190-196229-238 1-124 26-35 50-66 99-113 DQHDILTGVYYGMDV (SEQ ID NO: 2921)I005F02 922 144-251 167-177 193-199 232-240 1-128 26-35 50-66 99-117VSPSYDILTGYYLPHAFDV (SEQ ID NO: 2849) I005F04 923 137-247 159-172188-194 227-236 1-121 26-35 50-65 98-110 TYYDILTGRFFDI (SEQ ID NO: 2866)I005F08 924 140-247 161-171 187-193 226-236 1-124 26-35 50-66 99-113PSYDILTGYLYYFDY (SEQ ID NO: 2850) I005G01 925 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 DLRYDILTGYHDAFDI (SEQ ID NO: 2890)I005G08 926 142-249 165-175 191-197 230-238 1-126 26-35 50-66 99-115GAYYDILTGYYPYGMDV (SEQ ID NO: 2860) I005H02 927 140-247 161-171 187-193226-236 1-124 26-35 50-66 99-113 GQYYDILTGYNWFDP (SEQ ID NO: 2857)I006B01 928 139-246 160-170 186-192 225-235 1-123 26-35 50-66 99-112SRDLLLFPHYGMDV (SEQ ID NO: 2133) I006C09 929 143-253 165-177 193-199232-242 1-127 26-35 50-66 99-116 GGYSSGWLRGGPYNWFDP (SEQ ID NO: 2967)I006D09 930 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114GDYDILTGYYIPLRDY (SEQ ID NO: 2792) I006E01 931 143-253 165-178 194-200233-242 1-127 26-35 50-68 101-116  NLFDVWTLPYYYYMDV (SEQ ID NO: 2965)I006E07 932 143-250 166-176 192-198 231-239 1-127 26-35 50-66 99-116ADYDILTGYSPLTYGMDV (SEQ ID NO: 2762) I006F01 933 140-250 162-175 191-197230-239 1-124 26-35 50-68 101-113  MYYDILTGHNFDY (SEQ ID NO: 2879)I006F02 934 142-253 164-176 192-198 231-242 1-126 26-35 50-66 99-115VSRDILTGNYYYYGMDV (SEQ ID NO: 2817) I006F07 935 143-253 165-177 193-199232-242 1-127 26-35 50-66 99-116 GGYSSGWLRGGPYNWFDP (SEQ ID NO: 2967)I006G01 936 146-253 169-179 195-201 234-242 1-130 26-35 50-68 101-119 AGGYYDILTGRDYYYGMDV (SEQ ID NO: 2877) I006G04 937 132-239 153-163179-185 218-228 1-116 26-35 50-66 99-105 RRYALDY (SEQ ID NO: 2920)I006H01 938 146-253 167-177 193-199 232-242 1-130 26-35 50-65 98-119DRGSYDILTGYYTPPHYYGMDV (SEQ ID NO: 2761) I006H02 939 143-253 165-177193-199 232-242 1-127 26-35 50-66 99-116 GGYSSGWLRGGPYNWFDP (SEQ ID NO:2967) I007A01 940 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I007A08 941 139-249 161-174190-196 229-238 1-123 26-35 50-66 99-114 SHYDILTGLNYWYFDY (SEQ ID NO:2746) I007A11 942 140-250 162-175 191-197 230-239 1-124 26-35 50-6699-113 ENYDFLTGYYGAFDI (SEQ ID NO: 2772) I007A12 943 144-251 165-175191-197 230-240 1-128 26-35 50-68 101-117  GIYDILTGYHWDGAFDI (SEQ ID NO:2892) I007B04 944 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I007C04 945 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I007C08 946 142-249 163-173 189-195 228-238 1-126 26-35 50-6598-115 IRLYCYSLTGYYPYGMDD (SEQ ID NO: 2810) I007C12 947 140-250 162-175191-197 230-239 1-124 26-35 50-66 99-113 TNYDILTGYYQGVDY (SEQ ID NO:2782) I007D07 948 140-247 161-171 187-193 226-236 1-124 26-35 50-6699-113 GQYYDILTGYNWFDP (SEQ ID NO: 2857) I007D08 949 144-251 165-175191-197 230-240 1-128 26-35 50-68 101-117  GIYDILTGYHWDDAFDI (SEQ ID NO:2872) I007E03 950 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I007E10 951 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 DFYDILTGYPLGGMDV (SEQ ID NO:2741) I007E11 952 144-251 165-175 191-197 230-240 1-128 26-35 50-6699-117 DLPYYDILTGYSLTSGMDV (SEQ ID NO: 2923) I007F06 953 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I007F08 954 143-253 165-178 194-200 233-242 1-127 26-35 50-6598-116 GRRYDILTGYYYYHHGMDV (SEQ ID NO: 2811) I007G07 955 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 SHYDILTGLNYWYFDL (SEQ ID NO:2166) I007G09 956 142-252 164-177 193-199 232-241 1-126 26-35 50-6699-115 DSGGDILTGYYMPYFDY (SEQ ID NO: 2847) I007G10 957 142-249 163-173189-195 228-238 1-126 26-35 50-65 98-115 VGLYYDILTGYYPSGMDV (SEQ ID NO:2805) I007H07 958 147-257 169-182 198-204 237-246 1-131 26-35 50-68101-120  SQAHYDILTGYYLWSYGMDV (SEQ ID NO: 2875) I007H11 959 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 ESYDILTGYRHYGMDL (SEQID NO: 2891) I008A02 960 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008A05 961 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I008A06 962 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008A07 963 142-249163-173 189-195 228-238 1-126 26-35 50-66 99-115 DREYDLLTGYYLHAFDM (SEQID NO: 2960) I008A12 964 140-250 162-175 191-197 230-239 1-124 26-3550-66 99-113 ENYDFLTGYYGAFDI (SEQ ID NO: 2772) I008B02 965 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I008B04 966 143-253 165-178 194-200 233-242 1-127 26-3550-66 99-116 DGSYDILTGYYIDNYMDV (SEQ ID NO: 2154) I008B05 967 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 DHYDILTGLYYYGMDV (SEQID NO: 2760) I008B06 968 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008B07 969 140-247163-173 189-195 228-236 1-124 24-33 48-64 97-113 GRRYDILTGYYKGPLDY (SEQID NO: 2902) I008B10 970 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 AYYDNLTGFLPYGMGV (SEQ ID NO: 2947) I008B11 971 144-254166-179 195-201 234-243 1-128 26-35 50-66 99-117 EGYDILTGYFLDYYHGMDV(SEQ ID NO: 2753) I008C06 972 141-251 163-176 192-198 231-240 1-12526-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008C08 973149-259 171-183 199-205 238-248 1-133 26-35 50-66 99-122GPRGGPYYDILTGYYLSLSDAFDI (SEQ ID NO: 2729) I008C09 974 142-249 163-173189-195 228-238 1-126 26-35 50-66 99-115 EYYDILTGYRDPYGMDV (SEQ ID NO:2973) I008D01 975 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008D02 976 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I008D03 977 144-254 166-179 195-201 234-243 1-128 26-35 50-6699-117 EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I008D04 978 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I008D05 979 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008D06 980 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I008D07 981 144-254 166-179 195-201 234-243 1-128 26-35 50-6699-117 DRGYYDILTGYYRGHGMDV (SEQ ID NO: 2837) I008D08 982 144-251 165-175191-197 230-240 1-128 26-35 50-66 99-117 DLPYYDILTGYSLTSGMDV (SEQ ID NO:2923) I008D12 983 144-254 166-179 195-201 234-243 1-128 26-35 50-6699-117 EEGFYDILTGYYGPGYFDY (SEQ ID NO: 2974) I008E01 984 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I008E02 985 137-247 159-172 188-194 227-236 1-121 20-31 46-6396-110 EGYDILTGYSKFLDY (SEQ ID NO: 2906) I008E03 986 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I008E04 987 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008E08 988 141-252 163-175191-197 230-241 1-125 26-35 50-66 99-114 SHYDILTGLNYWYFDL (SEQ ID NO:2166) I008E09 989 143-253 165-178 194-200 233-242 1-127 26-35 50-6699-116 ERADYDILTGYYFYDMDV (SEQ ID NO: 2833) I008E12 990 141-251 163-176192-198 231-240 1-125 26-37 52-67 100-114  FRYDILTSYYYGMDV (SEQ ID NO:2734) I008F03 991 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008F06 992 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I008F07 993 143-250 164-174 190-196 229-239 1-127 26-35 50-6598-116 GRRYDILTGYYYYHHGMDV (SEQ ID NO: 2811) I008F08 994 143-253 165-178194-200 233-242 1-127 26-35 50-66 99-116 GHYDILTGYDDYYYGMDV (SEQ ID NO:2844) I008F09 995 133-243 155-168 184-190 223-232 1-117 26-35 50-6598-106 HDILTGFDY (SEQ ID NO: 2904) I008F10 996 140-247 161-171 187-193226-236 1-124 26-35 50-66 99-113 SGYDILTGYLYGMDV (SEQ ID NO: 2934)I008F11 997 144-251 165-175 191-197 230-240 1-128 26-35 50-68 101-117 APYDILTGYSDYYGMDV (SEQ ID NO: 2968) I008G02 998 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I008G03 999 140-247 161-171 187-193 226-236 1-124 26-35 50-66 99-113GDYDPLTGYSFGVDV (SEQ ID NO: 2941) I008G04 1000 143-253 165-178 194-200233-242 1-127 26-35 50-65 98-116 EGSYDILTGYYVGVGRMDV (SEQ ID NO: 2171)I008G05 1001 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117DGYYDILTGGFYYYYGMDV (SEQ ID NO: 2899) I008G11 1002 136-246 158-171187-193 226-235 1-120 26-35 50-66 99-109 AYYDILTGLDY (SEQ ID NO: 2966)I008G12 1003 143-253 165-178 194-200 233-242 1-127 26-35 50-66 99-116DQQYDILTGYYIHYGMDV (SEQ ID NO: 2964) I008H02 1004 141-248 164-174190-196 229-237 1-125 26-35 50-66 99-114 DQVDLLLMDHNYYMDV (SEQ ID NO:2918) I008H03 1005 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I008H06 1006 143-253 165-178194-200 233-242 1-127 26-35 50-65 98-116 EGSYDILTGYYVGVGRMDV (SEQ ID NO:2171) I008H09 1007 143-253 165-178 194-200 233-242 1-127 26-35 50-6699-116 DQQYDILTGYYIHYGMDV (SEQ ID NO: 2964) I008H11 1008 141-248 164-174190-196 229-237 1-125 26-35 50-66 99-114 TKYDILTGYYYYYMDV (SEQ ID NO:2856) I012B03 1009 140-249 163-175 191-197 230-238 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I012B06 1010 140-251 163-176192-198 231-240 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I012B10 1011 140-251 163-175 191-197 230-240 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I012C03 1012 142-255 165-178194-200 233-244 1-126 26-35 50-66 99-115 TDRFGAKDVTSRWGMDV (SEQ ID NO:2814) 1012C06 1013 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I012C09 1014 140-250 164-174190-196 229-239 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I012D12 1015 145-256 168-180 196-202 235-245 1-129 26-35 50-6699-118 DRGGNYDILTGYYFHHGVDV (SEQ ID NO: 2914) I012E07 1016 140-252164-176 192-198 231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQID NO: 2174) I012E08 1017 139-250 162-174 190-196 229-239 1-123 26-3550-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755) I012E09 1018 140-247163-173 189-195 228-236 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQID NO: 2174) I012F05 1019 140-249 163-173 189-195 228-238 1-124 26-3449-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I012F12 1020 140-251164-176 192-198 231-240 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQID NO: 2174) I012G03 1021 140-252 164-176 192-198 231-241 1-124 26-3449-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I012G05 1022 139-250163-173 189-195 228-239 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ IDNO: 2755) I012G10 1023 139-251 162-175 191-197 230-240 1-123 26-35 50-6699-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755) I012H09 1024 140-249 163-173189-195 228-238 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I013A10 1025 147-259 170-182 198-204 237-248 1-131 26-35 50-6699-120 SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I013A12 1026 147-256171-181 197-203 236-245 1-131 26-35 50-66 99-120 SSPPKWYDALTGHSSYHSAMDV(SEQ ID NO: 2159) I013B04 1027 147-256 172-182 198-204 237-245 1-13126-35 50-66 99-120 SSPPKWYDALTGDSSYHSAMDV (SEQ ID NO: 2165) I013B09 1028147-257 171-181 197-203 236-246 1-131 26-35 50-66 99-120SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I013C02 1029 147-258 170-182198-204 237-247 1-131 26-35 50-66 99-120 SSPPKWYDALTGDSSYRSAMDV (SEQ IDNO: 2818) I013G04 1030 137-249 161-173 189-195 228-238 1-121 26-35 50-6699-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I013D02 1031 137-248 160-173189-195 228-237 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136)I013D03 1032 147-259 170-183 199-205 238-248 1-131 26-35 50-66 99-120SSPPKWYDALTGDSSYHSAMDV (SEQ ID NO: 2165) I013D10 1033 145-257 168-181197-203 236-246 1-129 26-35 50-66 99-118 GLRHVTLFGTGTRGHFYMDV (SEQ IDNO: 2789) I013E02 1034 147-259 170-183 199-205 238-248 1-131 26-35 50-6699-120 GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2809) I013E05 1035 137-249162-173 189-195 228-238 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ IDNO: 2136) I013E09 1036 147-260 170-183 199-205 238-249 1-131 26-35 50-6699-120 SSPPKWYDALTGDSSYHSAMDV (SEQ ID NO: 2165) I013F03 1037 137-248160-172 188-194 227-237 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ IDNO: 2136) I013F04 1038 147-258 170-182 198-204 237-247 1-131 26-35 50-6699-120 SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I013F07 1039 145-260170-185 201-207 240-249 1-129 26-35 50-66 99-118 AATTSQKHNKYAYYFYGMDV(SEQ ID NO: 2131) I013F09 1040 137-248 160-172 188-194 227-237 1-12126-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I013F10 1041 147-259170-183 199-205 238-248 1-131 26-35 50-66 99-120 SSPPKWYDALTGHSSYHSAMDV(SEQ ID NO: 2159) I013H04 1042 147-258 170-182 198-204 237-247 1-13126-35 50-66 99-120 SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I013H07 1043147-259 170-183 199-205 238-248 1-131 26-35 50-66 99-120GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2809) I014A12 1044 143-253 165-178194-200 233-242 1-127 24-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ IDNO: 2158) I014C06 1045 141-254 164-177 193-200 233-243 1-125 26-35 50-6699-114 GDYDILTGYPAECFQI (SEQ ID NO: 2854) I014C10 1046 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I014C12 1047 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I014E06 1048 140-252 164-176192-198 231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I014F02 1049 141-251 166-176 192-198 231-240 1-125 26-37 52-67100-114  AGYDLLTGYPFYFDS (SEQ ID NO: 2757) I016A08 1050 144-251 165-175191-197 230-240 1-128 26-35 50-66 99-117 EVRNYDLLTRSYLAGPLDN (SEQ ID NO:2751) I016A09 1051 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I016C02 1052 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I016C03 1053 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I016C05 1054 148-255 169-179195-201 234-244 1-132 26-35 50-66 99-121 VQMDSEYYDLLTGINVGPYYFDY (SEQ IDNO: 2132) I016C09 1055 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I016C11 1056 148-255 169-179195-201 234-244 1-132 26-35 50-66 99-121 VQMDSEYYDLLTGINVGPYYFDY (SEQ IDNO: 2132) IO16D10 1057 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I016D11 1058 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I016E03 1059 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I016E04 1060 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I016F03 1061 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I016F11 1062 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I016G01 1063 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I016G06 1064 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I016G12 1065 148-255 169-179 195-201 234-244 1-132 26-35 50-6699-121 VQMDSEYYDLLTGINVGPYYFDY (SEQ ID NO: 2132) I016H10 1066 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I017A06 1067 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I017A07 1068 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I017A11 1069 140-253 162-175 191-197 233-242 1-124 25-3449-65 98-113 ATYDPLTGYSFDGLDI (SEQ ID NO: 2157) I017E12 1070 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I017G03 1071 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I017G07 1072 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I017H01 1073 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I018A02 1074 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I018A04 1075 144-254 166-179 195-201 234-243 1-128 26-3550-66 99-117 EGSYDILTGYYVGVGRMDV (SEQ ID NO: 2171) I018A05 1076 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I018A11 1077 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I018B02 1078 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I018B08 1079 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I018C04 1080 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I018D02 1081 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I018E06 1082 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I018E08 1083 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I018F04 1084 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I018G06 1085 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I018H07 1086 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I019E05 1087 144-254 166-179 195-201 234-243 1-128 26-3550-66 99-117 ERHYYDILTGYQTGYGMDV (SEQ ID NO: 2784) I019F06 1088 144-254166-179 195-201 234-243 1-128 26-35 50-66 99-117 ERHYYDILTGYQTGYGMDV(SEQ ID NO: 2784) I019G12 1089 143-253 165-178 194-200 233-242 1-12724-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I020D01 1090137-247 159-171 187-193 226-236 1-121 26-35 50-66 99-110 DRETKVGYGMDV(SEQ ID NO: 2945) I020D05 1091 143-253 165-178 194-200 233-242 1-12724-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I020E10 1092143-253 165-178 194-200 233-242 1-127 24-33 48-64 97-116EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I020G12 1093 143-253 165-178194-200 233-242 1-127 24-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ IDNO: 2158) I020H06 1094 143-253 165-178 194-200 233-242 1-127 24-33 48-6497-116 EGGNYHILTGYYIGNGAFDI (SEQ ID NO: 2896) I020H10 1095 143-253165-178 194-200 233-242 1-127 24-33 48-64 97-116 EGENYDILTGYYIGNGAFDI(SEQ ID NO: 2903) I021A11 1096 143-253 165-178 194-200 233-242 1-12724-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I021B01 1097143-253 165-178 194-200 233-242 1-127 24-33 48-64 97-116EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I021C11 1098 143-253 165-178194-200 233-242 1-127 24-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ IDNO: 2158) I021D12 1099 137-247 159-171 187-193 226-236 1-121 26-35 50-6699-110 DRETKVGYGMDV (SEQ ID NO: 2945) I021E10 1100 143-253 165-178194-200 233-242 1-127 24-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI (SEQ IDNO: 2158) I021G02 1101 143-253 165-178 194-200 233-242 1-127 24-33 48-6497-116 EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I022A08 1102 142-249163-173 189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQID NO: 2135) I022B01 1103 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I022B10 1104 141-248164-174 190-196 229-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQID NO: 2179) I022C02 1105 142-249 163-173 189-195 228-238 1-126 26-3550-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I022C04 1106 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I022C08 1107 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I022D06 1108 142-249163-173 189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQID NO: 2135) I022E08 1109 142-249 163-173 189-195 228-238 1-126 26-3550-66 99-115 ASYYDILTGYYKGAFDI (SEQ ID NO: 2855) I022F01 1110 142-249163-173 189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQID NO: 2135) I022F04 1111 142-249 163-173 189-195 228-238 1-126 26-3550-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I022F12 1112 140-247161-171 187-193 226-236 1-124 26-35 50-66 99-113 GDYDILTGTYYYIDV (SEQ IDNO: 2859) I022G11 1113 142-249 163-173 189-195 228-238 1-126 26-35 50-6699-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I023D01 1114 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 SHYDILTGLNYWYFDL (SEQ ID NO:2166) I023D04 1115 142-249 163-173 189-195 228-238 1-126 26-35 50-6699-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I024B04 1116 140-247 161-171187-193 226-236 1-124 26-35 50-66 99-113 VYYDILTGYNLFFDY (SEQ ID NO:2177) I024D01 1117 142-249 163-173 189-195 228-238 1-126 26-35 50-6699-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I024F06 1118 142-249 163-173189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO:2135) I024H01 1119 142-249 163-173 189-195 228-238 1-126 26-35 50-6699-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I024H07 1120 142-249 163-173189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO:2135) I025A01 1121 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I025A04 1122 140-251 163-175191-197 230-240 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I025A07 1123 140-249 163-173 189-195 228-238 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I025B01 1124 133-244 156-168184-190 223-233 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175)I025B10 1125 140-253 164-176 192-198 233-242 1-124 26-35 50-66 99-113DNYDILTGYSRRFDP (SEQ ID NO: 2942) I025B12 1126 140-251 163-176 192-198231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852)I025C07 1127 140-251 163-176 192-198 231-240 1-124 26-34 49-65 98-113ELGSSIVGATTGALDM (SEQ ID NO: 2852) I025D11 1128 140-252 164-176 192-198231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I025E04 1129 142-252 164-176 192-198 231-241 1-126 26-35 50-66 99-115PLGITAVRGAKTDAFGI (SEQ ID NO: 2929) I025E05 1130 140-251 163-175 191-197230-240 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I025E07 1131 140-252 164-176 192-198 231-241 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I025E10 1132 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I025F01 1133 139-251 162-175 191-197 230-240 1-123 26-35 50-66 99-112RYGDPFYYYYYMNV (SEQ ID NO: 2755) I025F08 1134 137-248 160-172 188-194227-237 1-121 26-35 50-66 99-110 GGSSQNFYGMDV (SEQ ID NO: 2884) I025G031135 140-252 164-176 192-198 231-241 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I025G08 1136 140-254 163-176 192-198231-243 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I025H02 1137 144-255 167-179 195-201 234-244 1-128 26-35 50-65 98-117AGSGFHDILTGYYKGGYFDY (SEQ ID NO: 2961) I026A01 1138 141-249 165-175191-197 230-238 1-125 26-35 50-66 99-114 GDYDILTGYPAECFQI (SEQ ID NO:2854) I026B01 1139 143-254 166-178 194-200 233-243 1-127 26-35 50-6699-116 GSVYDILTGTYYKSGMGV (SEQ ID NO: 2733) I026B06 1140 140-251 163-176192-198 231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO:2852) I026C06 1141 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I026C10 1142 138-249 161-174190-196 229-238 1-122 26-34 49-65 98-111 RYGDPFYYYYYMNV (SEQ ID NO:2755) I026C11 1143 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I026D09 1144 139-252 162-175191-197 230-241 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO:2755) I026E04 1145 140-252 164-176 192-198 231-241 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I026E06 1146 140-251 163-175191-197 230-240 1-124 26-35 50-66 99-113 GYDDILTGYIMALDY (SEQ ID NO:2821) I026E09 1147 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I026F01 1148 140-251 163-176192-198 231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO:2852) I026F09 1149 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I026F12 1150 140-256 163-176192-202 237-245 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO:2852) I026G08 1151 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I026G10 1152 140-251 163-176192-198 231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO:2852) I026G11 1153 143-255 166-179 195-201 234-244 1-127 26-35 50-6699-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800) I026H02 1154 139-251 162-175191-197 230-240 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO:2755) I026H06 1155 140-251 163-175 191-197 230-240 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I026H10 1156 144-255 167-179195-201 234-244 1-128 26-35 50-66 99-117 GGEYDILTGYYFGLGVYDY (SEQ ID NO:2170) I027A09 1157 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I027B02 1158 139-250 162-174190-196 229-239 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO:2755) I027B05 1159 140-250 163-176 192-198 230-239 1-124 26-34 49-6598-113 ELGSSIVGATTGALDM (SEQ ID NO: 2852) I027C08 1160 138-249 161-174190-196 229-238 1-122 26-34 49-63 96-111 ELGSSIVGATTGALDM (SEQ ID NO:2852) I027D02 1161 141-250 164-174 190-196 229-239 1-125 26-35 50-6699-114 DPFGAVPGYYYYAMDV (SEQ ID NO: 2826) I027E03 1162 140-251 163-176192-198 231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO:2852) I027E05 1163 140-252 164-176 192-198 231-241 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I027F04 1164 144-252 167-176192-198 231-241 1-128 26-35 50-66 99-117 GPWYDPLFPPSGRHYGLDV (SEQ ID NO:2793) I027F05 1165 140-254 163-176 192-198 231-243 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I027F11 1166 140-251 163-176192-198 231-240 1-124 26-34 49-65 98-113 ELGSSIVGATTGALDM (SEQ ID NO:2852) I027G06 1167 140-253 164-176 192-198 233-242 1-124 26-35 50-6699-113 DNYDILTGYSRRFDP (SEQ ID NO: 2942) I027G07 1168 140-250 164-174190-196 229-239 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I027H03 1169 141-252 164-176 192-198 231-241 1-125 26-35 50-6699-114 GDYDILTGYPAECFQI (SEQ ID NO: 2854) I028A04 1170 143-250 164-174190-196 229-239 1-127 26-35 50-66 99-116 DMYYDILTGYYTGLAFDM (SEQ ID NO:2880) I028A07 1171 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 VLNYDILTGYYYGMDV (SEQ ID NO: 2832) I028B08 1172 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I028B10 1173 148-258 170-183 199-205 238-247 1-132 26-35 50-68101-121  DFGYYDILTGYYIGAFYAFDI (SEQ ID NO: 2861) I028C01 1174 142-250165-175 191-197 230-239 1-126 26-37 52-69 102-115  GGHTCIIPTCHMGG (SEQID NO: 2796) I028C04 1175 143-253 165-178 194-200 233-242 1-127 26-3550-66 99-116 DMYYDILTGYYTGLAFDM (SEQ ID NO: 2880) I028C08 1176 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I028D04 1177 140-247 163-173 189-195 228-236 1-124 26-3550-65 98-113 ATQDILTGYLYSGMDV (SEQ ID NO: 2977) I028D05 1178 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 EHYDILTGYSLLGMDV (SEQID NO: 2907) I028D12 1179 143-250 164-174 190-196 229-239 1-127 26-3550-66 99-116 DGYYDILTGYSVYYGMDV (SEQ ID NO: 2938) I028E06 1180 143-253165-178 194-200 233-242 1-127 26-35 50-65 98-116 EGSYDILTGYYVGVGRMDV(SEQ ID NO: 2171) I028E07 1181 141-248 162-172 188-194 227-237 1-12526-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I028E08 1182141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I028F06 1183 146-256 168-180 196-202235-245 1-130 26-35 50-66 99-119 DDRRGYYDILTGYYRFGSFDI (SEQ ID NO: 2901)I028F08 1184 134-244 156-169 185-191 224-233 1-118 26-35 50-66 99-107DIDIGGDDS (SEQ ID NO: 2954) I028G08 1185 141-251 163-176 192-198 231-2401-125 26-35 50-66 99-114 VSGYNSGYFESYDMDV (SEQ ID NO: 2732) I028G09 1186144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I028G10 1187 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I028H02 1188 142-249 165-175 191-197 230-238 1-126 26-37 52-69102-115  SGEPCITLACNLGG (SEQ ID NO: 2797) I028H03 1189 148-256 169-179195-201 234-245 1-132 26-35 50-66 99-121 DASEYYDILTGYYLATGRNWFDP (SEQ IDNO: 2888) I028H06 1190 145-255 167-180 196-202 235-244 1-129 26-35 50-6699-118 DPSPYYDILTGYFLPYYMDV (SEQ ID NO: 2843) I028H09 1191 140-250162-175 191-197 230-239 1-124 26-35 50-68 101-113  EIDDILTGYYMDV (SEQ IDNO: 2905) I029A10 1192 139-246 160-170 186-192 225-235 1-123 26-35 50-6598-112 MNYDILTGLVNWFDP (SEQ ID NO: 2786) I029A12 1193 137-247 159-171187-193 226-236 1-121 26-35 50-68 101-110  RDILTGFYDS (SEQ ID NO: 2933)I029B11 1194 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I029C08 1195 144-254 166-179 195-201234-243 1-128 26-35 50-66 99-117 EGSYDILTGYYVGVGRMDV (SEQ ID NO: 2171)I029E10 1196 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I029F08 1197 144-254 166-179195-201 234-243 1-128 26-35 50-66 99-117 EVRNYDLLTRSYLAGPLDN (SEQ ID NO:2751) I029G08 1198 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 GYYDILTGYQSDAFDI (SEQ ID NO: 2927) I030A02 1199 142-253 165-177193-199 232-242 1-126 26-35 50-66 99-115 TERFGAKDVTARWGMDV (SEQ ID NO:2874) I030A03 1200 140-253 163-175 191-197 230-242 1-124 26-35 50-6699-113 ENYDILTGYYNFFDY (SEQ ID NO: 2737) I030A04 1201 140-252 163-176192-198 231-241 1-124 26-35 50-66 99-113 RQYDILTGYYGGFDY (SEQ ID NO:2958) I030A05 1202 140-249 163-175 191-197 230-238 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030A09 1203 139-250 162-174190-196 229-239 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO:2755) I030A12 1204 139-249 163-173 189-195 228-238 1-123 26-35 50-6699-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755) I030B06 1205 139-249 163-173189-195 228-238 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO:2755) I030B08 1206 140-247 163-173 189-195 228-236 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM SE ID NO: 2174) I030B10 1207 141-251 165-175191-197 230-240 1-125 26-35 50-66 99-114 ELGHREGGYWYSPYNV (SEQ ID NO:2838) I030C03 1208 139-252 162-175 191-197 230-241 1-123 26-35 50-6699-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755) I030C06 1209 146-256 169-182198-204 237-245 1-130 26-35 50-68 101-119  DPGNYDILTGYYYYYGMDV (SEQ IDNO: 2935) I030C08 1210 133-244 156-168 184-190 223-233 1-117 26-35 50-6699-106 SGPGWFDP (SEQ ID NO: 2870) I030C09 1211 140-251 163-175 191-197230-240 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I030C10 1212 140-250 163-175 191-197 230-239 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030C11 1213 139-251 162-175 191-197230-240 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755)I030C12 1214 133-244 156-168 184-190 223-233 1-117 26-35 50-66 99-106SGPGWFDP (SEQ ID NO: 2870) I030D07 1215 139-249 163-173 189-195 228-2381-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755) I030D12 1216140-251 163-175 191-197 230-240 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030E02 1217 139-251 162-175 191-197230-240 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755)I030E05 1218 140-252 164-176 192-198 231-241 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030E07 1219 140-251 165-176 192-198231-240 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I030E08 1220 140-251 163-175 191-197 230-240 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030E09 1221 140-252 163-176 192-198231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I030E10 1222 139-250 162-174 190-196 229-239 1-123 26-35 50-66 99-112RYGDPFYYYYYMNV (SEQ ID NO: 2755) I030F02 1223 141-252 164-176 192-198231-241 1-125 26-37 52-67 100-114  AGYDLLTGYPFYFDS (SEQ ID NO: 2757)I030F05 1224 140-251 163-175 191-197 230-240 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030F06 1225 139-251 162-175 191-197230-240 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755)I030F08 1226 140-254 163-176 192-198 231-243 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030F09 1227 140-253 164-176 192-198231-242 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I030F11 1228 139-250 162-174 190-196 229-239 1-123 26-35 50-66 99-112RYGDPFYYYYYMNV (SEQ ID NO: 2755) I030F12 1229 140-251 163-175 191-197230-240 1-124 26-35 50-66 99-113 DNYDILTGYSRRFDP (SEQ ID NO: 2942)I030G03 1230 140-256 163-176 192-202 237-245 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030G07 1231 139-251 162-175 191-197230-240 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755)I030G09 1232 140-251 164-174 190-196 229-240 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I030H05 1233 145-255 168-181 197-203236-244 1-129 26-35 50-66 99-118 DRGGNYDILTGYYFHHGVDV (SEQ ID NO: 2914)I030H06 1234 146-258 170-182 198-204 239-247 1-130 26-37 52-69 102-119 ATKSYDILTRMYYYHMDV (SEQ ID NO: 2748) I030H10 1235 140-253 163-176192-198 231-242 1-124 26-35 50-66 99-113 DNYDILTGYSRRFDP (SEQ ID NO:2942) I030H11 1236 140-252 164-176 192-198 231-241 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I031A01 1237 137-248 160-173189-195 228-237 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136)I031A03 1238 141-251 166-176 192-198 231-240 1-125 26-35 50-66 99-114PYYDPLTAYTFQYFGN (SEQ ID NO: 2806) I031A08 1239 147-258 170-182 198-204237-247 1-131 26-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO:2809) I031A12 1240 146-257 169-181 197-203 236-246 1-130 26-35 50-6699-119 GREDTDKVKPWDRYYHYYMDV (SEQ ID NO: 2972) I031B03 1241 136-246159-172 188-194 227-235 1-120 26-35 50-68 101-109  GLGHTDSDS (SEQ ID NO:2959) I031B06 1242 142-253 165-177 193-199 232-242 1-126 26-35 50-6699-115 AKGYYYDSSGASDVFDV (SEQ ID NO: 2871) I031B07 1243 147-258 170-182198-204 237-247 1-131 26-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV (SEQ IDNO: 2809) I031B08 1244 147-260 171-183 199-205 238-249 1-131 26-35 50-6699-120 SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I031B09 1245 147-258170-182 198-204 237-247 1-131 26-35 50-66 99-120 SNPPKWYDALTGHSSYHSAMDV(SEQ ID NO: 2840) I031B11 1246 137-248 160-172 188-194 227-237 1-12126-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I031B12 1247 147-259170-183 199-205 238-248 1-131 26-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV(SEQ ID NO: 2809) I031C01 1248 137-248 160-172 188-194 227-237 1-12126-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I031C02 1249 141-253164-177 193-199 232-242 1-125 26-35 50-66 99-114 PFYDTLTSYVFQYFDH (SEQID NO: 2137) I031C04 1250 147-260 171-183 199-205 238-249 1-131 26-3550-66 99-120 GRKDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2813) I031C08 1251137-248 161-171 187-193 226-237 1-121 26-35 50-66 99-110 GYDSSAFRAFDI(SEQ ID NO: 2136) I031C11 1252 147-257 171-181 197-203 236-246 1-13126-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2809) I031D01 1253145-256 168-180 196-202 235-245 1-129 26-35 50-66 99-118AATTSQKHNKYAYYFYGMDV (SEQ ID NO: 2131) I031D04 1254 137-248 160-172188-194 227-237 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136)I031D06 1255 147-258 170-182 198-204 237-247 1-131 26-35 50-66 99-120GREDTDKVKLWDRYYHYYYMDV (SEQ ID NO: 2807) I031D08 1256 144-257 167-180196-202 235-246 1-128 26-35 50-66 99-117 VRPKLRYFDWLSRHDAFDL (SEQ ID NO:2820) I031D09 1257 137-247 161-171 187-193 226-236 1-121 26-35 50-6699-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I031D11 1258 147-256 171-181197-203 236-245 1-131 26-35 50-66 99-120 SSPPKWYDALTGDSSYHSAMDV (SEQ IDNO: 2165) I031D12 1259 144-254 168-178 194-200 233-243 1-128 26-35 50-6699-117 DKAHGEYGRDYYYYYGMDV (SEQ ID NO: 2735) I031E01 1260 147-258170-182 198-204 237-247 1-131 26-35 50-66 99-120 SSPPKWYDALTGHSSYHSAMDV(SEQ ID NO: 2159) I031E05 1261 147-257 171-181 197-203 236-246 1-13126-35 50-66 99-120 SGPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2848) I031E07 1262147-259 170-182 198-204 237-248 1-131 26-35 50-66 99-120SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I031E08 1263 147-259 170-183199-205 238-248 1-131 26-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV (SEQ IDNO: 2809) I031E09 1264 137-246 162-173 189-195 228-235 1-121 26-35 50-6699-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I031E10 1265 147-258 170-182198-204 237-247 1-131 26-35 50-66 99-120 SSPPKWYDALTGDSSYHSAMDV (SEQ IDNO: 2165) I031E11 1266 147-258 170-182 198-204 237-247 1-131 26-35 50-6699-120 SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I031F01 1267 137-248160-172 188-194 227-237 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ IDNO: 2136) I031F04 1268 137-246 162-172 188-194 227-235 1-121 26-35 50-6699-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I031F06 1269 135-247 159-171187-193 226-236 1-119 26-35 50-66 99-108 DTVRSGGMDV (SEQ ID NO: 2804)I031F10 1270 147-259 170-183 199-205 238-248 1-131 26-35 50-66 99-120GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2809) I031F11 1271 144-255 167-179195-201 234-244 1-128 26-35 50-66 99-117 DKAHGEYGRDYYYYYGMDV (SEQ ID NO:2735) I031F12 1272 137-249 160-172 188-194 227-238 1-121 26-35 50-6699-110 GYDSSAFRAFDI (SEQ ID NO: 2136) I031G01 1273 137-248 160-172188-194 227-237 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136)I031G03 1274 147-258 170-182 198-204 237-247 1-131 26-35 50-66 99-120SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I031G05 1275 147-259 170-183199-205 238-248 1-131 26-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV (SEQ IDNO: 2809) I031G06 1276 147-258 170-182 198-204 237-247 1-131 26-35 50-6699-120 GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2809) I031G07 1277 147-259171-183 199-205 238-248 1-131 26-35 50-66 99-120 SSPPKWYDALTGDSSYHSAMGV(SEQ ID NO: 2816) I031G09 1278 147-263 170-183 199-209 244-252 1-13126-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2809) I031G12 1279145-256 168-180 196-202 235-245 1-129 26-35 50-66 99-118AATTSQKHNKYAYYFYGMDV (SEQ ID NO: 2131) I031H01 1280 137-250 160-173189-195 228-239 1-121 26-35 50-66 99-110 GYDSSAFRAFDI (SEQ ID NO: 2136)I031H02 1281 142-255 165-178 194-200 233-244 1-126 26-35 50-66 99-115AKGYYYDSSGASDVFDV (SEQ ID NO: 2871) I031H03 1282 147-260 170-183 199-205238-249 1-131 26-35 50-66 99-120 GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO:2809) I031H06 1283 144-257 167-179 195-201 234-246 1-128 26-35 50-6699-117 DKAHGEYGRDYYYYYGMDV (SEQ ID NO: 2735) I031H09 1284 144-255167-179 195-201 234-244 1-128 26-35 50-66 99-117 DKAHGEYGRDYYYYYGMDV(SEQ ID NO: 2735) I031H10 1285 143-256 166-179 195-201 234-245 1-12726-35 50-66 99-116 DRGYTGYDRLVGGYYFDF (SEQ ID NO: 2931) I031H11 1286135-246 158-170 186-192 225-235 1-119 26-35 50-66 99-108 DTVRSGGMDV (SEQID NO: 2804) I033A08 1287 144-254 166-179 195-201 234-243 1-128 26-3752-69 102-117  DRYDILTGYYYYGMDV (SEQ ID NO: 2129) I033B11 1288 144-254166-179 195-201 234-243 1-128 26-37 52-69 102-117  DRYDILTGYYYYGMDV (SEQID NO: 2129) I033C01 1289 144-254 166-179 195-201 234-243 1-128 26-3550-66 99-117 EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I033C08 1290 142-249163-173 189-195 228-238 1-126 26-35 50-66 99-115 EMGYDILTGYYLNYMDV (SEQID NO: 2862) I033D02 1291 138-245 161-171 187-193 226-234 1-122 26-3550-66 99-111 GDYDILTGYYMDV (SEQ ID NO: 2781) I033D03 1292 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I033D05 1293 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I033D11 1294 140-247161-171 187-193 226-236 1-124 26-35 50-66 99-113 VKRDILTGYVEGMDV (SEQ IDNO: 2869) I033D12 1295 144-254 166-179 195-201 234-243 1-128 26-35 50-6699-117 GGPHYDILTGYYMAVGFDI (SEQ ID NO: 2962) I033E01 1296 139-249161-173 189-195 228-238 1-123 26-35 50-66 99-112 DIDARLAALDAFDI (SEQ IDNO: 2794) I033E06 1297 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATHDPLTGYSFDGFDI (SEQ ID NO: 2780) I033E11 1298 143-253 165-177193-199 232-242 1-127 26-35 50-66 99-116 HRSRSCSSTSCRNDAFDI (SEQ ID NO:2770) I033E12 1299 142-249 163-173 189-195 228-238 1-126 26-35 50-6699-115 EMGYDILTGYYLNYMDV (SEQ ID NO: 2862) I033F03 1300 139-246 160-170186-192 225-235 1-123 26-35 50-66 99-112 EGAADYLNGQYFQD (SEQ ID NO:2768) I033F08 1301 145-256 167-179 195-201 234-245 1-129 26-35 50-6699-118 QKVYYDILTGYNYYYYGMDV (SEQ ID NO: 2767) I033F10 1302 144-254166-179 195-201 234-243 1-128 26-35 50-66 99-117 EVRNYDLLTRSYLAGPLDN(SEQ ID NO: 2751) I033F12 1303 134-241 155-165 181-187 220-230 1-11826-35 50-66 99-107 DIDIGGDDS (SEQ ID NO: 2954) I033G01 1304 143-253165-178 194-200 233-242 1-127 24-33 48-64 97-116 EGGNYDILTGYYIGNGAFDI(SEQ ID NO: 2158) I033G03 1305 142-249 163-173 189-195 228-238 1-12626-35 50-66 99-115 PQGVTLVRGAETDAFAI (SEQ ID NO: 2925) I033G08 1306141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I033H04 1307 140-247 161-171 187-193226-236 1-124 25-34 49-65 98-113 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I037A05 1308 139-246 160-170 186-192 225-235 1-123 26-35 50-66 99-112SRDLLLFPHYGMDV (SEQ ID NO: 2133) I037B03 1309 141-251 163-175 191-197230-240 1-125 26-35 50-66 99-114 SHYDILTRLNYWYFDL (SEQ ID NO: 2950)I037B04 1310 144-251 167-177 193-199 232-240 1-128 26-35 50-66 99-117DPGYYDILTGYFHRYGMDV (SEQ ID NO: 2922) I037C04 1311 142-252 164-177193-199 232-241 1-126 26-35 50-65 98-115 ENGDYDILTGQTFYGMDV (SEQ ID NO:2752) I037C06 1312 141-249 163-173 189-195 228-238 1-125 26-35 50-6699-114 LYYDILTGYHWDAFDI (SEQ ID NO: 2882) I037C08 1313 140-250 162-175191-197 230-239 1-124 26-35 50-66 99-113 DGIDILLVPAALMDV (SEQ ID NO:2160) I037D11 1314 136-246 158-171 187-193 226-235 1-120 26-35 50-6699-109 SQWLEHDVFDI (SEQ ID NO: 2864) I037E06 1315 144-251 165-175191-197 230-240 1-128 26-35 50-66 99-117 DRRDYDLLTRYYYYYGMDV (SEQ ID NO:2928) I037F04 1316 144-251 165-175 191-197 230-240 1-128 26-35 50-6598-117 KQRGDYDILTGYQLGYAFDI (SEQ ID NO: 2808) I037G01 1317 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 SHYDILTRLNYWYFDL (SEQID NO: 2950) I037G03 1318 146-256 168-181 197-203 236-245 1-130 26-3550-66 99-119 DLGSFYDILTALRLENYGMDV (SEQ ID NO: 2963) I037G10 1319140-250 162-175 191-197 230-239 1-124 26-35 50-66 99-113 DYYDILTKLPYGMDV(SEQ ID NO: 2975) I042A07 1320 144-251 167-177 193-199 232-240 1-12826-35 50-66 99-117 VSPSYDILTGYYLPHAFDV (SEQ ID NO: 2849) I042A10 1321142-249 165-175 191-197 230-238 1-126 26-35 50-65 98-115GPRYYDILTGYRYNWFDP (SEQ ID NO: 2801) I042B03 1322 140-247 161-171187-193 226-236 1-124 26-35 50-66 99-113 DIDDILTGYVLGMDV (SEQ ID NO:2924) I042B12 1323 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 SHYDILTGLNYWYFDL (SEQ ID NO: 2166) I042D01 1324 136-246 158-171187-193 226-235 1-120 26-35 50-66 99-109 QQWLPYDAFDI (SEQ ID NO: 2839)I042D03 1325 140-250 162-175 191-197 230-239 1-124 26-35 50-68 101-113 AYYDILTGYFFDI (SEQ ID NO: 2873) I042D10 1326 142-252 164-177 193-199232-241 1-126 26-35 50-65 98-115 ERADYDILTGYYFYGMDV (SEQ ID NO: 2802)I042E10 1327 147-257 169-182 198-204 237-246 1-131 26-37 52-69 102-120 ERPYYDILTGYTVTYGMDV (SEQ ID NO: 2798) I042E11 1328 140-247 161-171187-193 226-236 1-124 26-35 50-66 99-113 DEYDILTGLLQGMDV (SEQ ID NO:2883) I042F08 1329 142-252 164-177 193-199 232-241 1-126 26-37 52-67100-115  GDYDILTGYPLHAFDI (SEQ ID NO: 2738) I042F12 1330 140-247 161-171187-193 226-236 1-124 26-35 50-66 99-113 DGYDILTGYYFGMDV (SEQ ID NO:2976) I042G08 1331 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 EHYDILTGYSLLGMDV (SEQ ID NO: 2907) I042G10 1332 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 SHYDILTGLNYWYFDL (SEQ ID NO:2166) I042H03 1333 143-253 165-178 194-200 233-242 1-127 26-35 50-6598-116 GSLYYDILTGYYIGNAFDI (SEQ ID NO: 2759) I043A03 1334 144-254166-179 195-201 234-243 1-128 26-35 50-66 99-117 DGYYDILTGGFYYYYGMDV(SEQ ID NO: 2899) I043B02 1335 142-249 163-173 189-195 228-238 1-12626-35 50-65 98-115 GGYYDILTGYLVYYGMDV (SEQ ID NO: 2744) I043B03 1336141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I043B06 1337 143-253 165-178 194-200233-242 1-127 26-35 50-66 99-116 DQQYDILTGYHIDYYMDV (SEQ ID NO: 2828)I043B07 1338 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I043B09 1339 143-253 165-178 194-200233-242 1-127 26-35 50-65 98-116 HVRDYDILTGYYRGHHFDY (SEQ ID NO: 2727)I043D11 1340 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I043E05 1341 143-250 164-174190-196 229-239 1-127 26-35 50-66 99-116 TESNYDILTGYYWPSMDV (SEQ ID NO:2940) I043F01 1342 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I043F04 1343 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I043F12 1344 143-250 164-174 190-196 229-239 1-127 26-35 50-6699-116 TESNYDILTGYYWPSMDV (SEQ ID NO: 2940) I043H07 1345 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I044A11 1346 144-251 165-175 191-197 230-240 1-128 26-35 50-68101-117  APYDILTGYSDYYGMDV (SEQ ID NO: 2968) I044B11 1347 139-249161-173 189-195 228-238 1-123 26-35 50-66 99-112 DSDARLAALDAFDI (SEQ IDNO: 2978) I044C09 1348 140-250 162-174 190-196 229-239 1-124 26-35 50-6699-113 GQFGVLPNYYYHMDV (SEQ ID NO: 2943) I044C10 1349 143-253 165-177193-199 232-242 1-127 26-35 50-66 99-116 DIKRYNSNWPYYDYYMDV (SEQ ID NO:2726) I044D03 1350 144-254 166-179 195-201 234-243 1-128 26-35 50-6699-117 DKQYYDILTGDPVEGGMDV (SEQ ID NO: 2889) I044D09 1351 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I044E07 1352 137-247 159-172 188-194 227-236 1-121 26-3550-66 99-110 AGSSLVTYGTDV (SEQ ID NO: 2825) I044E11 1353 143-253 165-178194-200 233-242 1-127 26-35 50-66 99-116 SDDYDILTGNYVGSLLDY (SEQ ID NO:2758) I044F07 1354 147-257 169-182 198-204 237-246 1-131 26-35 50-6699-120 DGRLSYDILTGYYARDYYGMDV (SEQ ID NO: 2912) I044G02 1355 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I044G07 1356 149-259 171-184 200-206 239-248 1-133 26-3550-66 99-122 DQNHPIYDILTGYYVPTGPLELKN (SEQ ID NO: 2845) I044H01 1357144-251 165-175 191-197 230-240 1-128 26-35 50-66 99-117EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I050A01 1358 141-253 164-177193-199 232-242 1-125 26-35 50-66 99-114 DMGYDILTGYYGAFDI (SEQ ID NO:2946) I050B12 1359 141-253 164-177 193-199 232-242 1-125 26-35 50-6699-114 DYYDVLTGFSLDGMDV (SEQ ID NO: 2829) I050C06 1360 140-248 165-175191-197 230-237 1-124 26-35 50-65 98-113 DHYDVLTGSYLQAFDV (SEQ ID NO:2728) I050C08 1361 141-253 164-177 193-199 232-242 1-125 26-37 52-67100-114  GRYDFLTGYLRNFDY (SEQ ID NO: 2731) I050E01 1362 140-252 163-176192-198 231-241 1-124 26-35 50-66 99-113 GHYDILTGYYFGFDY (SEQ ID NO:2886) I050E10 1363 137-248 160-172 188-194 227-237 1-121 26-35 50-6699-110 DMKVYYKYALDV (SEQ ID NO: 2823) I050H08 1364 141-253 164-177193-199 232-242 1-125 26-35 50-66 99-114 DLRYDILTGYHDAFDI (SEQ ID NO:2890) I051A04 1365 147-258 170-183 199-205 238-247 1-131 26-35 50-6699-120 SSPPKWYDALTGHSSYHSAMDV (SEQ ID NO: 2159) I051A08 1366 141-252164-176 192-198 231-241 1-125 26-35 50-66 99-114 HRRARVVVPVPGAMDV (SEQID NO: 2930) I051A12 1367 143-250 164-174 190-196 229-239 1-127 26-3550-66 99-116 DGSYDILTGYYIDNYMDV (SEQ ID NO: 2154) I051B08 1368 142-253165-177 193-199 232-242 1-126 26-36 51-67 100-115  RSMIVVTTAPYDAFDL (SEQID NO: 2785) I051C06 1369 135-246 158-170 186-192 225-235 1-119 26-3550-66 99-108 DTVRSGGMDV (SEQ ID NO: 2804) I051G12 1370 143-250 164-174190-196 229-239 1-127 26-35 50-66 99-116 DGSYDILTGYYIDNYMDV (SEQ ID NO:2154) I055A05 1371 133-244 156-169 185-191 224-233 1-117 26-35 50-6699-106 SGPGWFDP (SEQ ID NO: 2870) I055A11 1372 133-244 156-169 185-191224-233 1-117 26-35 50-66 99-106 SGPGWFDP (SEQ ID NO: 2870) I061A03 1373140-251 163-176 192-198 231-240 1-124 26-34 49-65 98-113ELGSSIVGATTGALDM (SEQ ID NO: 2852) I061A04 1374 141-251 165-175 191-197230-240 1-125 26-35 50-66 99-114 GDYDILTGYPAECFQI (SEQ ID NO: 2854)I061A08 1375 140-253 164-176 192-198 233-242 1-124 26-35 50-66 99-113DNYDILTGYSRRFDP (SEQ ID NO: 2942) I061A09 1376 140-252 164-176 192-198231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I061A10 1377 140-249 163-173 189-195 228-238 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I061B07 1378 140-252 163-176 192-198231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I061B09 1379 143-253 165-178 194-200 233-242 1-127 24-33 48-64 97-116EGGNYDILTGYYIGNGAFDI (SEQ ID NO: 2158) I061B12 1380 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I061C12 1381 138-248 160-173 189-195 228-237 1-122 26-35 50-6699-111 TYYDILTGYHFDY (SEQ ID NO: 2788) I061D01 1382 137-247 159-172188-194 227-236 1-121 26-35 50-68 101-110  GPGVIGNYDY (SEQ ID NO: 2749)I061D03 1383 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I061D04 1384 140-247 161-171 187-193226-236 1-124 26-35 50-66 99-113 AVLRYSAGLQGAFDI (SEQ ID NO: 2970)I061D07 1385 141-248 164-174 190-196 229-237 1-125 26-35 50-66 99-114VSGYNSGYFESYDMDV (SEQ ID NO: 2732) I061D09 1386 141-248 162-172 188-194227-237 1-125 26-35 50-66 99-114 LNLEKTVVRGFGYFDL (SEQ ID NO: 2952)I061D10 1387 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114DHYDILTGLYYYGMDV (SEQ ID NO: 2760) I061E01 1388 141-248 162-172 188-194227-237 1-125 26-35 50-66 99-114 LNLEKTVVRGFGYFDL (SEQ ID NO: 2952)I061E05 1389 142-251 163-175 191-197 230-240 1-126 26-35 50-66 99-115GGELVWFGESDYYGMDV (SEQ ID NO: 2787) I061E09 1390 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I061E12 1391 133-240 154-164 180-186 219-229 1-117 26-35 50-66 99-106SQRLFIDS (SEQ ID NO: 2842) I061F01 1392 146-256 168-181 197-203 236-2451-130 26-35 50-66 99-119 DRYYDILTGYYIPGLDDAFDI (SEQ ID NO: 2887) I061F091393 139-246 160-170 186-192 225-235 1-123 26-35 50-66 99-112DSDARLAALDAFDI (SEQ ID NO: 2978) I061F10 1394 145-252 166-176 192-198231-241 1-129 26-35 50-66 99-118 EESYYDILTGYYVHYYGMDV (SEQ ID NO: 2743)I061F11 1395 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYYFDGFDI (SEQ ID NO: 2949) I061G01 1396 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I061G03 1397 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114AYYDILTGFLPYDMDL (SEQ ID NO: 2771) I061G09 1398 144-254 166-179 195-201234-243 1-128 26-35 50-66 99-117 EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751)I061G10 1399 143-253 165-178 194-200 233-242 1-127 26-35 50-65 98-116EGSYDILTGYYVGVGRMDV (SEQ ID NO: 2171) I061G11 1400 137-247 159-171187-193 226-236 1-121 26-35 50-68 101-110  RDILTGFYDS (SEQ ID NO: 2933)I061H05 1401 142-252 164-177 193-199 232-241 1-126 26-37 52-67 100-115 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I064A05 1402 142-249 163-173 189-195228-238 1-126 26-35 50-68 101-115  DFYDILTGYQHGMDV (SEQ ID NO: 2919)I064A11 1403 138-248 160-173 189-195 228-237 1-122 26-35 50-66 99-111HSKEYNWNYALDY (SEQ ID NO: 2754) I064B01 1404 138-248 160-173 189-195228-237 1-122 26-35 50-66 99-111 TRMDVLTRYYSDF (SEQ ID NO: 2750) I064B021405 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117AFEDYDILTGYYHHDAFDI (SEQ ID NO: 2911) I064B12 1406 133-243 155-168184-190 223-232 1-117 26-35 50-66 99-106 PSYHYMDV (SEQ ID NO: 2740)I064C06 1407 145-255 167-180 196-202 235-244 1-129 26-35 50-66 99-118VNADYDILTGYPRDYYGMDV (SEQ ID NO: 2819) I064D01 1408 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I064D02 1409 146-256 168-181 197-203 236-245 1-130 26-35 50-6699-119 EDATYYDILTGYYMGSYGMDV (SEQ ID NO: 2763) I064E01 1410 143-250166-176 192-198 231-239 1-127 26-35 50-66 99-116 ETRKYTSSPPYNYYYMDV (SEQID NO: 2736) I064E02 1411 140-251 162-174 190-196 229-240 1-124 26-3550-66 99-113 RDYDILTGYSRGFDP (SEQ ID NO: 2725) I064E03 1412 144-254166-179 195-201 234-243 1-128 26-35 50-66 99-117 DGIYDILTTLVSYYNGMDV(SEQ ID NO: 2775) I064E07 1413 140-250 162-175 191-197 230-239 1-12426-35 50-65 98-113 GERDILTGYYLDGMDV (SEQ ID NO: 2948) I064E08 1414140-250 162-174 190-196 229-239 1-124 26-35 50-66 99-113 ERGSYSSGYSGAFDV(SEQ ID NO: 2898) I064F05 1415 142-252 164-177 193-199 232-241 1-12626-35 50-66 99-115 ESGGYSYGSRDYYGMDV (SEQ ID NO: 2836) I064F08 1416145-252 166-176 192-198 231-241 1-129 26-35 50-66 99-118DRGVGYDILTGRTYYYGMDV (SEQ ID NO: 2900) I064G06 1417 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I065A12 1418 143-253 165-178 194-200 233-242 1-127 26-35 50-6699-116 DVSGHDILTGYSYRYFDV (SEQ ID NO: 2795) I065C04 1419 139-249 161-173189-195 228-238 1-123 26-35 50-66 99-112 GQKNYYESSGYLEH (SEQ ID NO:2916) I065C09 1420 140-250 162-174 190-196 229-239 1-124 26-35 50-6699-113 GDYDILTGYYSHFDY (SEQ ID NO: 2908) I065E02 1421 141-248 164-174190-196 229-237 1-125 26-35 50-66 99-114 AYDYDILTGYSYYFDY (SEQ ID NO:2895) I065E04 1422 135-245 157-169 185-191 224-234 1-119 26-35 50-6699-108 GMGDHYGMDV (SEQ ID NO: 2161) I065F03 1423 137-247 159-172 188-194227-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773) I065G061424 135-242 156-166 182-188 221-231 1-119 26-35 50-66 99-108 GMGDHYGMDV(SEQ ID NO: 2161) I065G07 1425 142-249 163-173 189-195 228-238 1-12626-35 50-66 99-115 GGNYDILTGYYIGAFDI (SEQ ID NO: 2824) I065G08 1426139-246 160-170 186-192 225-235 1-123 26-35 50-66 99-112 SRDLLLFPHYGMDV(SEQ ID NO: 2133) I065H06 1427 144-254 166-179 195-201 234-243 1-12826-35 50-66 99-117 GYEYYDILTGYNELGAFDI (SEQ ID NO: 2851) I066A03 1428144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117DGTYYDILTGYYNQYGMDV (SEQ ID NO: 2915) I066A08 1429 137-247 159-171187-193 226-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773)I066A09 1430 135-245 157-169 185-191 224-234 1-119 26-35 50-66 99-108GMGDHYGMDV (SEQ ID NO: 2161) I066A10 1431 142-252 164-177 193-199232-241 1-126 26-35 50-66 99-115 DRGYDILTGYYYYGMDV (SEQ ID NO: 2876)I066A11 1432 143-253 165-178 194-200 233-242 1-127 26-35 50-66 99-116EVRDYDILTGYYISYMDV (SEQ ID NO: 2778) I066B02 1433 135-242 156-166182-188 221-231 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO: 2161)I066B08 1434 137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110AGSSLMTYGTDV (SEQ ID NO: 2773) I066B10 1435 142-252 164-177 193-199232-241 1-126 26-35 50-66 99-115 GLYFEDTNYRHGDAFDI (SEQ ID NO: 2790)I066C02 1436 135-245 157-169 185-191 224-234 1-119 26-35 50-66 99-108GMGDHYGMDV (SEQ ID NO: 2161) I066C11 1437 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I066C12 1438 135-242 156-166 182-188 221-231 1-119 26-35 50-66 99-108GMGDHYGMDV (SEQ ID NO: 2161) I066D06 1439 140-250 162-175 191-197230-239 1-124 26-35 50-66 99-113 ENYDFLTGYYGAFDI (SEQ ID NO: 2772)I066D08 1440 138-248 160-173 189-195 228-237 1-122 26-35 50-66 99-111HSKEYNWNYALDY (SEQ ID NO: 2754) I066D11 1441 144-254 166-179 195-201234-243 1-128 26-35 50-66 99-117 ERSQFDFLTGVDRYHPMDV (SEQ ID NO: 2956)I066D12 1442 139-249 161-174 190-196 229-238 1-123 26-35 50-66 99-112EGAADYLNGQYFQH (SEQ ID NO: 2815) I066E06 1443 137-247 159-171 187-193226-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773) I066E121444 135-242 156-166 182-188 221-231 1-119 26-35 50-66 99-108 GMGDHYGMDV(SEQ ID NO: 2161) I066G05 1445 142-249 163-173 189-195 228-238 1-12626-35 50-66 99-115 GLYFEDTNYRHGDAFDI (SEQ ID NO: 2790) I066G08 1446141-248 164-174 190-196 229-237 1-125 26-35 50-66 99-114VYYDILTGHPTYGMDV (SEQ ID NO: 2791) I066G10 1447 144-254 166-178 194-200233-243 1-128 26-35 50-68 101-117  GIYDILTGYHWDDAFDI (SEQ ID NO: 2872)I066G12 1448 143-254 165-177 193-199 232-243 1-127 26-35 50-66 99-116ESTYDILTGSYHDYGLDV (SEQ ID NO: 2822) I066H04 1449 143-253 165-178194-200 233-242 1-127 26-35 50-65 98-116 DRLHYDILTGHQTDDAFDI (SEQ ID NO:2885) I067A07 1450 144-254 166-179 195-201 234-243 1-128 26-35 50-6699-117 VLTNYDILTGYYREDAFDM (SEQ ID NO: 2939) I067A11 1451 135-245157-170 186-192 225-234 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO:2161) I067B08 1452 149-259 171-184 200-206 239-248 1-133 26-35 50-6699-122 DRGASNYDILTGYYAPAQGVAFDI (SEQ ID NO: 2969) I067C08 1453 148-258170-183 199-205 238-247 1-132 26-37 52-69 102-121  EGAHYDILTGHNYYHYGMDV(SEQ ID NO: 2747) I067C09 1454 143-253 165-178 194-200 233-242 1-12726-35 50-66 99-116 ETRKYTSSPPYNYYYMDV (SEQ ID NO: 2736) I067D07 1455137-247 159-171 187-193 226-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV(SEQ ID NO: 2773) I067E01 1456 140-248 164-174 190-196 229-238 1-12426-35 50-66 99-113 DQHDILTGVYYGMDV (SEQ ID NO: 2921) I067E06 1457135-245 157-169 185-191 224-234 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQID NO: 2161) I067E07 1458 150-260 172-184 200-206 239-249 1-134 26-3550-67 100-123  DYPGSEYDILTGYLFGYYYYGMDV (SEQ ID NO: 2926) I067E11 1459141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I067G03 1460 140-250 162-175 191-197230-239 1-124 26-35 50-66 99-113 ARRVGVLGGKNAFEI (SEQ ID NO: 2765)I067G05 1461 140-250 162-174 190-196 229-239 1-124 26-35 50-66 99-113DQHDILTGGYYGMDV (SEQ ID NO: 2894) I067G12 1462 141-252 163-176 192-198231-241 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I067H05 1463 146-256 168-180 196-202 235-245 1-130 26-35 50-68 101-119 EGTYYDILTGYYPLGYFDY (SEQ ID NO: 2936) I067H06 1464 135-245 157-169185-191 224-234 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO: 2161)I068C09 1465 137-248 160-172 188-194 227-237 1-121 26-35 50-66 99-110GGSSQNFYGMDV (SEQ ID NO: 2884) I068G03 1466 143-254 166-178 194-200233-243 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800)I068G04 1467 142-252 165-178 194-200 233-241 1-126 26-35 50-66 99-115GVVWVAYGDVGIYGFDV (SEQ ID NO: 2937) I068G07 1468 140-251 164-174 190-196229-240 1-124 26-35 50-66 99-113 HDYYIMTAAHYYYDS (SEQ ID NO: 2909)I068G08 1469 143-254 166-178 194-200 233-243 1-127 26-35 50-66 99-116GIGYDLLTGYFTGSPLDY (SEQ ID NO: 2846) I070F07 1470 140-247 161-171187-193 226-236 1-124 26-35 50-66 99-113 DFYDILTGYHDAFDI (SEQ ID NO:2910) I070G05 1471 140-250 162-175 191-197 230-239 1-124 26-35 50-68101-113  DVDDILTGYSWDY (SEQ ID NO: 2867) I070H02 1472 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO:2179) I071A01 1473 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 AAYDPLTGYSFDGFDI (SEQ ID NO: 2783) I071A03 1474 143-250 164-174190-196 229-239 1-127 26-35 50-66 99-116 DMHYDILTGYYTGLAFDM (SEQ ID NO:2917) I071B08 1475 142-252 166-176 192-198 231-241 1-126 27-36 51-67100-115  GGYDILTQYPAEFFHP (SEQ ID NO: 2764) I071E01 1476 138-248 160-173189-195 228-237 1-122 26-35 50-66 99-111 DFGVIGDYRPFDY (SEQ ID NO: 2777)I071F11 1477 135-245 157-169 185-191 224-234 1-119 26-35 50-66 99-108SSNPVYGLDV (SEQ ID NO: 2957) I071G11 1478 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I071H08 1479 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I074A02 1480 141-250 164-174 190-196229-239 1-125 26-35 50-66 99-114 DDRDILTNYYLEYFQH (SEQ ID NO: 2868)I074A08 1481 147-259 170-182 198-204 237-248 1-131 26-35 50-66 99-120SSPPKWYDALTGDSSYHSAMDV (SEQ ID NO: 2165) I074D10 1482 144-253 168-178194-200 233-242 1-128 26-35 50-66 99-117 DKTLGDQLVEAYYYDGMDV (SEQ ID NO:2776) I074E01 1483 144-255 168-178 194-200 233-244 1-128 26-35 50-6699-117 LGRTSRDLLTGYHFYNMDV (SEQ ID NO: 2944) I074E02 1484 140-250164-174 190-196 229-239 1-124 26-35 50-66 99-113 DDYDILTGSLYYFDS (SEQ IDNO: 2803) I074E08 1485 143-259 166-179 195-205 240-248 1-127 26-35 50-6699-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800) I074F12 1486 140-250 164-174190-196 229-239 1-124 26-35 50-66 99-113 DRADILTGYNDAFDI (SEQ ID NO:2739) I074H06 1487 139-251 162-175 191-197 230-240 1-123 26-35 50-6699-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755) I074H07 1488 143-253 167-177193-199 232-242 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO:2800) I074H08 1489 142-254 165-178 194-200 233-243 1-126 26-35 50-6699-115 VSNDILTGWGGYNWFDP (SEQ ID NO: 2955) I075A07 1490 143-253 167-177193-199 232-242 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO:2800) I075B01 1491 133-244 156-168 184-190 223-233 1-117 26-35 50-6699-106 DQGRYLDL (SEQ ID NO: 2175) I075B04 1492 133-247 156-169 185-191224-236 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175) I075B06 1493140-252 163-175 191-197 230-241 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I075B08 1494 143-257 166-179 195-201234-246 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800)I075B09 1495 141-252 164-176 192-198 231-241 1-125 26-35 50-66 99-114TYYDILTGYYAEYFQH (SEQ ID NO: 2932) I075B12 1496 140-251 163-176 192-198231-240 1-124 26-35 50-66 99-113 SDYDILTGYYWVPAV (SEQ ID NO: 2812)I075C01 1497 147-259 170-183 199-205 238-248 1-131 26-35 50-66 99-120GREDTDKVKPWDRYFHYYYMDV (SEQ ID NO: 2835) I075C05 1498 133-244 156-168184-190 223-233 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175)I075D05 1499 143-253 168-179 195-201 234-242 1-127 26-35 50-66 99-116GTGYDILTGYYMGSVFDP (SEQ ID NO: 2897) I075D07 1500 141-252 164-176192-198 231-241 1-125 26-35 50-66 99-114 SYYDILTGYYHTPLDY (SEQ ID NO:2853) I075D08 1501 140-251 163-175 191-197 230-240 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I075E01 1502 143-253 167-177193-199 232-242 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO:2800) I075E03 1503 148-261 172-184 200-206 239-250 1-132 28-37 52-68101-121  GGGYDILTGYSYPYLYYGLDV (SEQ ID NO: 2865) I075E04 1504 143-255166-179 195-201 234-244 1-127 26-35 50-66 99-116 GRGYDVLTGYFTGSPLDY (SEQID NO: 2881) I075E05 1505 140-252 163-176 192-198 231-241 1-124 26-3449-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I075E10 1506 140-252163-176 192-198 231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQID NO: 2174) I075E11 1507 133-244 156-168 184-190 223-233 1-117 26-3550-66 99-106 SGPGWFDP (SEQ ID NO: 2870) I075E12 1508 142-254 165-178194-200 233-243 1-126 26-35 50-66 99-115 TDRFGAKDVTARWGMDV (SEQ ID NO:2979) I075F02 1509 144-253 168-178 194-200 233-242 1-128 26-35 50-6699-117 EQGYDILTGYYPEGGWFDP (SEQ ID NO: 2834) I075F04 1510 141-251164-176 192-198 231-240 1-125 26-37 52-67 100-114 AGYDLLTGYPFYFDS (SEQID NO: 2757) I075F06 1511 144-254 168-178 194-200 233-243 1-128 26-3550-66 99-117 GRNYYDFLTGYNFNLGLDY (SEQ ID NO: 2830) I075F07 1512 140-251163-175 191-197 230-240 1-124 26-35 50-66 99-113 ENYDSLTGYYNYFDY (SEQ IDNO: 2971) I075F08 1513 133-244 156-168 184-190 223-233 1-117 26-35 50-6699-106 DQRKAQDI (SEQ ID NO: 2779) I075F09 1514 145-257 169-181 197-203236-246 1-129 26-35 50-66 99-118 LKAPYYDLLTGYHLPKWFDT (SEQ ID NO: 2953)I075F10 1515 133-243 157-167 183-189 222-232 1-117 26-35 50-66 99-106DQGRYLDL (SEQ ID NO: 2175) I075F11 1516 133-245 156-169 185-191 224-2341-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175) I075G05 1517 140-252163-175 191-197 230-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQID NO: 2174) I075G07 1518 140-252 163-175 191-197 230-241 1-124 26-3550-66 99-113 GRYYDMLTRGGYFDY (SEQ ID NO: 2858) I075G08 1519 140-252163-176 192-198 231-241 1-124 26-35 50-66 99-113 RQYDILTGYYGGFDY (SEQ IDNO: 2958) I075G11 1520 141-253 164-177 193-199 232-242 1-125 26-35 50-6699-114 TDYDILTGYPMGYFDP (SEQ ID NO: 2173) I075G12 1521 133-245 156-169185-191 224-234 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175)I075H02 1522 143-254 166-178 194-200 233-243 1-127 26-35 50-66 99-116GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800) I075H03 1523 133-245 156-169185-191 224-234 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175)I075H06 1524 133-244 156-168 184-190 223-233 1-117 26-35 50-66 99-106DQGRYLDL (SEQ ID NO: 2175) I075H08 1525 143-254 166-179 195-201 234-2431-127 26-35 50-66 99-116 GSGYDLLTGYFTGSPLDY (SEQ ID NO: 2766) I076A011526 142-253 166-176 192-198 231-242 1-126 26-35 50-66 99-115DRRRDDLTGYLYDAFDS (SEQ ID NO: 2878) I076A03 1527 135-247 159-171 187-193226-236 1-119 26-35 50-68 101-108  GYDTAMQY (SEQ ID NO: 2951) I076A061528 133-245 156-168 184-190 223-234 1-117 26-35 50-66 99-106 DQGRYLDL(SEQ ID NO: 2175) I076A07 1529 139-250 162-174 190-196 229-239 1-12326-35 50-66 99-112 DRRDILTGSNFGQD (SEQ ID NO: 2913) I076A08 1530 142-253166-176 192-198 231-242 1-126 26-35 50-66 99-115 MGHYDILTGYRHYGMDV (SEQID NO: 2831) I076B01 1531 143-257 167-179 195-201 236-246 1-127 26-3550-66 99-116 GSGYDLLTGYFTGSPLDY (SEQ ID NO: 2766) I076B03 1532 133-245156-169 185-191 224-234 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO:2175) I076B07 1533 133-243 157-167 183-189 222-232 1-117 26-35 50-6699-106 DQGRYLDL (SEQ ID NO: 2175) I076B08 1534 141-252 166-177 193-199232-241 1-125 26-35 50-66 99-114 PYYDPLTAYTFQYFGN (SEQ ID NO: 2806)I076C04 1535 140-250 164-174 190-196 229-239 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I076C10 1536 140-251 163-175 191-197230-240 1-124 26-35 50-66 99-113 GRYYDMLTRGGYFDY (SEQ ID NO: 2858)I076D01 1537 141-252 164-176 192-198 231-241 1-125 26-35 50-66 99-114LDYDILTGYYPSGFDY (SEQ ID NO: 2799) I076D08 1538 140-251 163-175 191-197230-240 1-124 26-37 52-67 100-113  RFYDLLTGYSAFDS (SEQ ID NO: 2756)I076D11 1539 143-255 166-179 195-201 234-244 1-127 26-35 50-66 99-116GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800) I076D12 1540 140-250 164-174190-196 229-239 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I076E04 1541 143-252 167-177 193-199 232-241 1-127 26-35 50-6699-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800) I076E07 1542 140-251 163-175191-197 230-240 1-124 26-35 50-66 99-113 EYYDVLTGLFYYMDV (SEQ ID NO:2841) I076E09 1543 141-253 164-177 193-199 232-242 1-125 26-35 50-6699-114 DDRDILTNYYLEYFQH (SEQ ID NO: 2868) I076E11 1544 143-254 166-179195-201 234-243 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO:2800) I076F01 1545 143-253 166-178 194-199 232-242 1-127 26-35 50-6699-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800) I076F03 1546 140-251 163-175191-197 230-240 1-124 26-36 51-66 99-113 GDYDVLTGYLRKLDY (SEQ ID NO:2742) I076F04 1547 133-245 157-169 185-191 224-234 1-117 26-35 50-6699-106 DQGRYLDL (SEQ ID NO: 2175) I076F08 1548 140-250 164-174 190-196229-239 1-124 26-36 51-66 99-113 VHYDILTGYLWAFDI (SEQ ID NO: 2730)I076F10 1549 140-252 163-175 191-197 230-241 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I076G09 1550 133-245 156-168 184-190223-234 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175) I076G10 1551140-251 163-175 191-197 230-240 1-124 26-35 50-66 99-113 GRYYDMLTRGGYFDY(SEQ ID NO: 2858) I076G11 1552 143-259 166-179 195-205 240-248 1-12726-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800) I076G12 1553146-257 169-181 197-203 236-246 1-130 26-35 50-66 99-119NGYYDILTGYYLWDYYYGMDV (SEQ ID NO: 2769) I076H02 1554 140-251 163-175191-197 230-240 1-124 26-35 50-66 99-113 ENYDSLTGYYNYFDY (SEQ ID NO:2971) I076H04 1555 141-251 165-175 191-197 230-240 1-125 26-35 50-6699-114 THYDILTGYYSHPLDY (SEQ ID NO: 2863) I076H05 1556 140-251 163-175191-197 230-240 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO:2174) I076H06 1557 140-252 163-176 192-198 231-241 1-124 26-35 50-6699-113 VPYDILTGYWGAFDV (SEQ ID NO: 2827) I076H09 1558 143-256 166-179195-201 234-245 1-127 26-35 50-66 99-116 GSGYDLLTGYFTGSPLDY (SEQ ID NO:2766) I076H10 1559 143-256 166-179 195-201 234-245 1-127 26-35 50-6699-116 GSGYDLLTGYFTGSPLDY (SEQ ID NO: 2766) I077D06 1560 140-250 162-175191-197 230-239 1-124 26-35 50-66 99-113 VYYDILTGYNLFFDY (SEQ ID NO:2177) I078B04 1561 140-250 162-175 191-197 230-239 1-124 26-35 50-6699-113 VYYDILTGYNLFFDY (SEQ ID NO: 2177) I078E10 1562 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO:2179) I002A01-K 1563 141-250 164-174 190-196 229-239 1-125 26-35 50-6699-114 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I002A01-R 1564 141-250 164-174190-196 229-239 1-125 26-35 50-66 99-114 ELGLSIVGATTGALDM (SEQ ID NO:2174) I026C04-K 1565 141-250 164-176 192-198 231-239 1-125 26-35 50-6699-114 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I026C04-R 1566 141-250 164-176192-198 231-239 1-125 26-35 50-66 99-114 ELGLSIVGATTGALDM (SEQ ID NO:2174) I067B10 1567 149-259 171-183 199-205 238-248 1-133 26-35 50-6699-122 DRGAPNYDILTGYYAPAQGVAFDI (SEQ ID NO: 2176) I068C06 1568 133-244156-169 185-191 224-233 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO:2175) I075F12 1569 133-244 156-168 184-190 223-233 1-117 26-35 50-6699-106 DQGRYLDL (SEQ ID NO: 2175) I003C06 1570 140-249 163-173 189-195228-238 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I025B06 1571 140-249 163-175 191-197 230-238 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I025B09 1572 140-249 163-175 191-197230-238 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I026C04 1573 140-249 163-175 191-197 230-238 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I027B12 1574 141-250 164-174 190-196229-239 1-125 26-34 49-65 99-114 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I030A10 1575 140-252 163-176 192-198 231-241 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I064C04 1576 147-257 169-182 198-204237-246 1-131 26-35 50-66 99-120 DGRLSYDILTGYYARDYYGMDD (SEQ ID NO:2188) I064C07 1577 134-241 157-167 183-189 222-230 1-118 26-35 50-6699-107 SEGTIFGVD (SEQ ID NO: 2178) I065D04 1578 144-254 166-179 195-201234-243 1-128 26-36 51-66 99-117 GKGYYDILTGYYRDNWFDP (SEQ ID NO: 2181)I065D08 1579 147-257 169-182 198-204 237-246 1-131 26-35 50-66 99-120TPSSVYDLLTGYYHYFYSYMDV (SEQ ID NO: 2189) I065F08 1580 135-242 158-168184-190 223-231 1-119 26-35 50-66 99-108 EKSAAGYFDY (SEQ ID NO: 2190)I067F05 1581 140-250 162-175 191-197 230-239 1-124 26-35 50-66 99-113ENYDSLTGYYGAFDI (SEQ ID NO: 2185) I068B04 1582 133-244 156-168 184-190223-233 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175) I068B08 1583140-252 163-175 191-197 231-241 1-124 26-34 49-65 98-113KLGLSIVGATTGALDM (SEQ ID NO: 2186) I068C08 1584 142-254 165-178 194-200233-243 1-126 26-35 50-66 99-115 EGMNDFINSHHYYTMDA (SEQ ID NO: 2182)I068F03 1585 139-251 162-175 191-197 230-240 1-123 26-35 50-66 99-112AGNEYGHTERPADY (SEQ ID NO: 2180) I069B07 1586 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179)I071B03 1587 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072B09 1588 141-248 162-172 188-194227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I073F04 1589 136-246 158-171 187-193 226-235 1-120 26-35 50-66 99-109SLATRPLGMDV (SEQ ID NO: 2184) I074B12 1590 140-252 164-176 192-198231-241 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174)I075A02 1591 140-251 163-175 191-197 230-240 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I075G01 1592 140-251 164-174 190-196229-240 1-124 26-35 50-66 99-113 DHFDTLTGYFRRLDS (SEQ ID NO: 2187)I078D02 1593 140-250 162-175 191-197 230-239 1-124 26-35 50-66 99-113VYYDILTGYNLFFDY (SEQ ID NO: 2177) I078D08 1594 144-251 165-175 191-197230-240 1-128 26-35 50-66 99-117 DAQSYYDILTGYQSYAFDI (SEQ ID NO: 2183)I078H08 1595 140-250 162-175 191-197 230-239 1-124 26-35 50-66 99-113VYYDILTGYNLFFDY (SEQ ID NO: 2177) I064A03 1596 150-257 171-181 197-203236-246 1-134 26-35 50-66 99-123 GPSTTYYDILTGYYTPYYYYYYMDV (SEQ ID NO:3014) I064B03 1597 145-255 167-179 195-201 234-244 1-129 26-37 52-67100-118  HVRDYDILTGYYRGHYFDY (SEQ ID NO: 2167) I064B05 1598 140-250162-174 190-196 229-239 1-124 26-35 50-66 99-113 ERGVVTAYGGDSFDL (SEQ IDNO: 2985) I064B11 1599 138-248 160-173 189-195 228-237 1-122 26-35 50-6699-111 DRGPGLLSSFFES (SEQ ID NO: 3033) I064C02 1600 146-256 168-180196-202 235-245 1-130 26-35 50-66 99-119 DEYYDILTGYQAPYYYYGMDV (SEQ IDNO: 3068) I064C03 1601 140-250 162-175 191-197 230-239 1-124 26-35 50-6699-113 ERGVVTAYGGDSFDL (SEQ ID NO: 2985) I064C11 1602 143-253 165-178194-200 233-242 1-127 26-35 50-65 98-116 DVTYHDILTGYAGHEAFDI (SEQ ID NO:3055) I064C12 1603 148-255 171-181 197-203 236-244 1-132 26-37 52-69102-12 1 ESGRYDILTGYYSGGGGMDV (SEQ ID NO: 3012) I064D03 1604 146-256168-181 197-203 236-245 1-130 26-35 50-66 99-119 DGANYDILTGYYTTTVYGMDV(SEQ ID NO: 3072) I064D04 1605 141-251 163-176 192-198 231-240 1-12526-35 50-66 99-114 RSYDILTGYYTYGMDV (SEQ ID NO: 3090) I064D06 1606134-244 156-169 185-191 224-233 1-118 26-35 50-66 99-107 EGSSGYLVG (SEQID NO: 2981) I064E05 1607 146-256 168-180 196-202 235-245 1-130 26-3752-67 100-119  KQRGDYDILTGYQLGYAFDI (SEQ ID NO: 2808) I064E06 1608145-255 167-180 196-202 235-244 1-129 26-35 50-66 99-118ERPGYDILTGYPSSIYGMDV (SEQ ID NO: 3053) I064F07 1609 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I064F09 1610 147-257 169-181 197-203 236-246 1-131 26-35 50-6699-120 DTLGYDILTGYPPPYYYYDMDV (SEQ ID NO: 2988) I064F10 1611 143-253165-177 193-199 232-242 1-127 22-31 46-62 95-116 DTLGYDILTGYPPPYYYYDMDV(SEQ ID NO: 2988) I064F11 1612 142-252 164-177 193-199 232-241 1-12626-35 50-65 98-115 GRHYYDILTGYYNEAFDI (SEQ ID NO: 3031) I064G01 1613140-250 162-175 191-197 230-239 1-124 26-35 50-66 99-113 NYYDVLTQSYYGMDV(SEQ ID NO: 3077) I064G04 1614 133-243 155-167 183-189 222-232 1-11726-35 50-66 99-106 DNSGTYGY (SEQ ID NO: 3084) I064G08 1615 138-245159-169 185-191 224-234 1-122 26-35 50-66 99-111 GGVTAGRSVYFDS (SEQ IDNO: 2990) I064G10 1616 140-250 162-175 191-197 230-239 1-124 26-35 50-6699-113 SPNGDYSGYAWGLEY (SEQ ID NO: 3085) I064G11 1617 138-248 160-173189-195 228-237 1-122 26-35 50-65 98-111 YFDGSGYYPVSFSY (SEQ ID NO:3064) I064G12 1618 139-249 161-173 189-195 228-238 1-123 26-35 50-6598-112 VNYDILTGLGYYFDY (SEQ ID NO: 3049) I064H03 1619 143-253 165-178194-200 233-242 1-127 26-37 52-67 100-116  SYYDILTGRPYTDAFDI (SEQ ID NO:2989) I064H04 1620 142-249 163-173 189-195 228-238 1-126 26-35 50-6699-115 PLGITAVRGAKTDAFGI (SEQ ID NO: 2929) I064H06 1621 149-256 170-180196-202 235-245 1-133 26-35 50-66 99-122 DRGASNYDILTGYYAPAQGVAFDI (SEQID NO: 2969) I065A02 1622 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I065A04 1623 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I065A06 1624 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I065A07 1625 144-254166-179 195-201 234-243 1-128 26-35 50-66 99-117 DGGGYDILTGYQYYYGMDV(SEQ ID NO: 2987) I065B01 1626 145-255 167-180 196-202 235-244 1-12926-35 50-65 98-118 WATYYDTLTGYRLKDHAGFDI (SEQ ID NO: 3017) I065B05 1627142-252 164-177 193-199 232-241 1-126 26-35 50-66 99-115SPGDDILTGYYKYYFDY (SEQ ID NO: 3032) I065B09 1628 146-253 167-177 193-199232-242 1-130 26-35 50-66 99-119 DAGESYDILTGYYVIEGYMDV (SEQ ID NO: 2986)I065B12 1629 139-249 161-174 190-196 229-238 1-123 26-35 50-66 99-112EGAADYLNGQYFQH (SEQ ID NO: 2815) I065C02 1630 136-246 158-170 186-192225-235 1-120 26-35 50-66 99-109 EGSWSGLDLDY (SEQ ID NO: 3007) I065C061631 141-253 163-175 191-197 230-242 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I065C08 1632 141-250 163-176 192-198231-239 1-125 26-35 50-66 99-114 VSGYNSGYFESYDMDV (SEQ ID NO: 2732)I065C10 1633 137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110QGGQYDSPPLDV (SEQ ID NO: 3002) I065D01 1634 142-252 164-177 193-199232-241 1-126 26-35 50-66 99-115 DRDYDILTDYSNYGMDV (SEQ ID NO: 3074)I065D03 1635 142-249 165-175 191-197 230-238 1-126 26-35 50-66 99-115APLYDILTGYYIGGNDY (SEQ ID NO: 3028) I065D05 1636 143-253 165-178 194-200233-242 1-127 26-35 50-66 99-116 DKDYDILTGYWRDELLDY (SEQ ID NO: 3040)I065D06 1637 142-252 164-177 193-199 232-241 1-126 26-35 50-66 99-115DPNYDILTGYYYYAMDV (SEQ ID NO: 3062) I065E01 1638 139-246 160-170 186-192225-235 1-123 26-35 50-66 99-112 EFDQLLARGHGMDV (SEQ ID NO: 3027)I065E05 1639 137-244 158-168 184-190 223-233 1-121 26-35 50-66 99-110AGSSLMTYGTDV (SEQ ID NO: 2773) I065E06 1640 146-256 168-181 197-203236-245 1-130 26-35 50-66 99-119 ARGSYDILTGYYRPGDGYFDY (SEQ ID NO: 3043)I065E08 1641 142-249 163-173 189-195 228-238 1-126 26-35 50-66 99-115GLYFEDTNYRHGDAFDI (SEQ ID NO: 2790) I065E09 1642 145-255 167-179 195-201234-244 1-129 26-35 50-65 98-118 ERSYYDILTGYSPRSKYGMDV (SEQ ID NO: 3021)I065E12 1643 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I065F04 1644 140-250 162-175 191-197230-239 1-124 26-35 50-66 99-113 ERGVVTAYGGDSFDL (SEQ ID NO: 2985)I065F05 1645 140-250 162-175 191-197 230-239 1-124 26-35 50-65 98-113RYSDALTGYSLGAFDV (SEQ ID NO: 3018) I065F07 1646 145-252 166-176 192-198231-241 1-129 26-38 53-69 102-118  GAYYDILTGYYPYGMDV (SEQ ID NO: 2860)I065F09 1647 143-250 164-174 190-196 229-239 1-127 26-35 50-66 99-116DYPIDVLTGRRTKNWFDP (SEQ ID NO: 3013) I065F12 1648 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 DQVDRLLMQYNYYMDA (SEQ ID NO:3047) I065G01 1649 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I065G09 1650 143-253 165-178194-200 233-242 1-127 26-35 50-68 101-116  DAYYDILTGWVYGMDV (SEQ ID NO:3030) I065G10 1651 140-247 161-171 187-193 226-236 1-124 26-36 51-6699-113 FRYDILTGYYYDMDV (SEQ ID NO: 2983) I065H05 1652 140-247 161-171187-193 226-236 1-124 26-35 50-66 99-113 EYYDILTGYSGAFDI (SEQ ID NO:2984) I065H07 1653 138-248 160-173 189-195 228-237 1-122 26-35 50-6699-111 TRMDVLTRYYSDF (SEQ ID NO: 2750) I066A05 1654 137-247 159-172188-194 227-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773)I066A06 1655 139-246 160-170 186-192 225-235 1-123 26-35 50-66 99-112EGAADYLNGQYFQH (SEQ ID NO: 2815) I066A12 1656 142-252 164-177 193-199232-241 1-126 26-35 50-66 99-115 DTRVIGIQLWERGAFDM (SEQ ID NO: 3080)I066B05 1657 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I066B11 1658 142-252 164-177 193-199232-241 1-126 26-35 50-66 99-115 PLGITAVRGAKTDAFGI (SEQ ID NO: 2929)I066C06 1659 144-254 166-178 194-200 233-243 1-128 26-35 50-65 98-117GRRYYDILTGYSLGRGEMDV (SEQ ID NO: 3009) I066C10 1660 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I066D02 1661 137-247 159-172 188-194 227-236 1-121 26-35 50-6699-110 AGTSLMNYGTDV (SEQ ID NO: 3048) I066D07 1662 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 GPYDVLTGYLSGNFDY (SEQ ID NO:2992) I066E01 1663 137-247 159-172 188-194 227-236 1-121 26-35 50-6699-110 QGGQYDSPPFDV (SEQ ID NO: 3001) I066E03 1664 149-259 171-184200-206 239-248 1-133 26-35 50-66 99-122 GEKARYYDILTGYYSAWGGYYMDV (SEQID NO: 3045) I066E04 1665 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 LNLEKTVIRGFGYFDL (SEQ ID NO: 3081) I066E05 1666 142-252164-177 193-199 232-241 1-126 26-35 50-66 99-115 VGGYDILTGYYLRGMDV (SEQID NO: 2997) I066E07 1667 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I066E09 1668 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I066F01 1669 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 SPYDTLTGYVYNGVDV (SEQ ID NO: 3058) I066F03 1670 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I066F04 1671 141-251 163-175 191-197 230-240 1-125 26-3550-66 99-114 VAAAGARTLGYFGMDV (SEQ ID NO: 3071) I066F07 1672 143-253165-178 194-200 233-242 1-127 26-35 50-66 99-116 DVSGHDILTGYSYRYFDV (SEQID NO: 2795) I066F08 1673 144-254 166-179 195-201 234-243 1-128 26-3550-66 99-117 SPMYYDRLTGFYPSGYFDS (SEQ ID NO: 3036) I066F11 1674 142-252164-177 193-199 232-241 1-126 26-35 50-66 99-115 GAYYDILTGYYPYGMDV (SEQID NO: 2860) I066F12 1675 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 GPSSAGTTIGLGSFDP (SEQ ID NO: 3005) I066G06 1676 143-250164-174 190-196 229-239 1-127 26-35 50-66 99-116 ETRKYTSSPPYNYYYMDV (SEQID NO: 2736) I066G07 1677 133-243 155-168 184-190 223-232 1-117 26-3045-61 94-106 DQFSVGGRHAFDL (SEQ ID NO: 3054) I066H02 1678 135-242156-166 182-188 221-231 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO:2161) I067A02 1679 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I067A03 1680 137-247 159-172188-194 227-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773)I067A06 1681 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I067A08 1682 137-247 159-171 187-193226-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773) I067A101683 140-250 162-175 191-197 230-239 1-124 26-35 50-66 99-113ERGVVTAYGGDSFDL (SEQ ID NO: 2985) I067B03 1684 142-253 164-177 193-199232-242 1-126 26-35 50-66 99-115 PLGITAVRGAKTDAFGI (SEQ ID NO: 2929)I067B04 1685 137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110AGSSLMTYGTDV (SEQ ID NO: 2773) I067C03 1686 133-244 156-169 185-191224-233 1-117 26-35 50-66 99-106 DWGHWFDP (SEQ ID NO: 2982) I067C05 1687137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110 SGSSLMTYGTDV(SEQ ID NO: 3015) I067C07 1688 141-251 163-176 192-198 231-240 1-12526-35 50-66 99-114 EPYDILTGYYGSYFDY (SEQ ID NO: 3041) I067C10 1689137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV(SEQ ID NO: 2773) I067C12 1690 142-252 164-177 193-199 232-241 1-12626-35 50-66 99-115 TYYDILTGYSGGGAFDY (SEQ ID NO: 3024) I067D01 1691136-246 158-171 187-193 226-235 1-120 26-35 50-66 99-109 GSRVRGVTPDL(SEQ ID NO: 3020) I067D03 1692 137-244 158-168 184-190 223-233 1-12126-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773) I067D05 1693 146-256168-180 196-202 235-245 1-130 26-35 50-66 99-119 ECSGSSCPARQPPYYQYYMDV(SEQ ID NO: 2993) I067D06 1694 137-244 158-168 184-190 223-233 1-12126-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773) I067D09 1695 142-252164-177 193-199 232-241 1-126 26-35 50-66 99-115 GAYYDILTGYYPYGMDV (SEQID NO: 2860) I067D12 1696 137-247 159-172 188-194 227-236 1-121 26-3550-66 99-110 QGGQYDSPPLDV (SEQ ID NO: 3002) I067E02 1697 137-247 159-172188-194 227-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773)I067E04 1698 142-252 164-176 192-198 231-241 1-126 26-35 50-66 99-115GAYYDILTGYYPYGMDV (SEQ ID NO: 2860) I067E05 1699 144-254 166-179 195-201234-243 1-128 26-35 50-66 99-117 DYRNYDILTGHPYYYGMDV (SEQ ID NO: 2996)I067F01 1700 141-248 164-174 190-196 229-237 1-125 26-35 50-66 99-114QHYDILTGYSQEPFDI (SEQ ID NO: 3022) I067F03 1701 144-254 166-179 195-201234-243 1-128 26-35 50-66 99-117 DQTYYDILTGHYYYYGMDV (SEQ ID NO: 3087)I067F04 1702 139-246 160-170 186-192 225-235 1-123 26-35 50-66 99-112EGAADYLNGQYFQH (SEQ ID NO: 2815) I067F08 1703 140-247 161-171 187-193226-236 1-124 26-35 50-66 99-113 LGYYDILTGYRSDDY (SEQ ID NO: 3029)I067F10 1704 137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110AGSSLMAYGTDV (SEQ ID NO: 3016) I067F11 1705 140-248 161-171 187-193226-237 1-124 26-35 50-66 99-113 ENYDFLTGYYGAFDI (SEQ ID NO: 2772)I067G01 1706 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I067G09 1707 137-247 159-171 187-193226-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773) I067H071708 144-251 165-175 191-197 230-240 1-128 26-35 50-66 99-117GGLYDILTGRPATDDAFDI (SEQ ID NO: 3035) I068A07 1709 142-254 165-178194-200 233-243 1-126 26-35 50-66 99-115 TDRFGAKDVTARWGMDV (SEQ ID NO:2979) I068E05 1710 147-257 170-183 199-205 238-246 1-131 26-35 50-6699-120 GREDTDKVKPWDRYYHYYYMDV (SEQ ID NO: 2809) I068E08 1711 133-247157-169 185-193 226-236 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO:2175) I068E11 1712 140-251 163-176 192-198 231-240 1-124 26-34 49-6598-113 ELGLSIVGATTGALDM (SEQ ID NO: 2174) I068F04 1713 141-252 164-176192-198 231-241 1-125 26-35 50-66 99-114 ELGHREGGYWYSPYNV (SEQ ID NO:2838) I068G05 1714 135-245 159-169 185-191 224-234 1-119 26-35 50-6698-108 KNMGASAAADF (SEQ ID NO: 3042) I068G06 1715 139-250 162-174190-196 229-239 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO:2755) I068G11 1716 146-258 169-182 198-204 237-247 1-130 26-35 50-6699-119 ESGSHYDLLTGLLVAANGFDV (SEQ ID NO: 3044) I069A09 1717 141-248164-174 190-196 229-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQID NO: 2179) I069A10 1718 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I069B06 1719 141-248164-174 190-196 229-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQID NO: 2179) I069B09 1720 139-249 161-174 190-196 229-238 1-123 26-3550-66 99-112 PYYDILTGYFAFDI (SEQ ID NO: 3026) I069B12 1721 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQID NO: 2179) I069C06 1722 143-250 164-174 190-196 229-239 1-127 26-3550-66 99-116 VLPHYDILTGYSQNWFDP (SEQ ID NO: 3000) I069C09 1723 143-250164-174 190-196 229-239 1-127 26-35 50-66 99-116 VLPHYDILTGYSQNWFDP (SEQID NO: 3000) I069D03 1724 142-249 163-173 189-195 228-238 1-126 26-3550-66 99-115 DGYYDILTGYSYYGMDV (SEQ ID NO: 2135) I069E09 1725 142-249163-173 189-195 228-238 1-126 26-35 50-66 99-115 DGYYDILTGYSYYGMDV (SEQID NO: 2135) I069E11 1726 140-247 161-171 187-193 226-236 1-124 26-3550-66 99-113 VYYDILTGYNLFFDY (SEQ ID NO: 2177) I069F05 1727 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQID NO: 2179) I069F07 1728 141-248 162-172 188-194 227-237 1-125 26-3550-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I069F12 1729 140-247161-171 187-193 226-236 1-124 26-35 50-66 99-113 GYYDILTGYYDAFDI (SEQ IDNO: 3051) I069G06 1730 142-249 163-173 189-195 228-238 1-126 26-35 50-6699-115 DGYYDILTGYSGYYMDV (SEQ ID NO: 3059) I069G08 1731 145-252 166-176192-198 231-241 1-129 26-35 50-66 99-118 DRLEYYDILTGYYYYYGMDV (SEQ IDNO: 3039) I069G11 1732 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I070A03 1733 141-248 164-174190-196 229-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO:2179) I070A09 1734 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I070B01 1735 144-254 166-179195-201 234-243 1-128 26-35 50-66 99-117 SQSDYDILTGYYYYYGMDV (SEQ ID NO:3038) I070B05 1736 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I070D03 1737 141-248 164-174190-196 229-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO:2179) I070D04 1738 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 MEYDILTSYYGGYFDY (SEQ ID NO: 3034) I070E01 1739 144-254 166-179195-201 234-243 1-128 26-35 50-66 99-117 SQSDYDILTGYYYYYGMDV (SEQ ID NO:3038) I070F01 1740 144-251 165-175 191-197 230-240 1-128 26-35 50-6699-117 SQSNYDILTGYYYYYGMDV (SEQ ID NO: 3067) I070G10 1741 141-248162-172 188-194 227-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQID NO: 2179) I071A06 1742 135-242 156-166 182-188 221-231 1-119 26-3550-66 99-108 GMGDHYGMDV (SEQ ID NO: 2161) I071B02 1743 135-245 157-170186-192 225-234 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO: 2161)I071D02 1744 137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110AGTSLMNYGTDV (SEQ ID NO: 3048) I071D08 1745 146-256 168-181 197-203236-245 1-130 26-37 52-66 99-119 VPYYYDTSGGYLGEYYYGMDV (SEQ ID NO: 3010)I071F01 1746 137-247 159-172 188-194 227-236 1-121 26-35 50-66 99-110AGTSLMNYGTDV (SEQ ID NO: 3048) I071G09 1747 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I072A01 1748 139-249 161-174 190-196 229-238 1-123 26-35 50-66 99-112SRDLLLFPHYGMDV (SEQ ID NO: 2133) I072A09 1749 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I072B02 1750 135-245 157-170 186-192 225-234 1-119 26-35 50-66 99-108GMGDHYGMDV (SEQ ID NO: 2161) I072B10 1751 137-247 159-172 188-194227-236 1-121 26-35 50-66 99-110 AGSSLMTYGTDV (SEQ ID NO: 2773) I072B111752 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072B12 1753 140-249 162-173 189-195228-238 1-124 26-35 50-66 99-113 ENYDYLTGYYGAFDI (SEQ ID NO: 2995)I072C05 1754 135-245 157-169 185-191 224-234 1-119 26-35 50-66 99-108GMGDHYGMDV (SEQ ID NO: 2161) I072C10 1755 141-248 162-172 188-194227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I072D01 1756 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072D05 1757 135-245 157-169 185-191224-234 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO: 2161) I072E011758 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072E04 1759 144-254 166-179 195-201234-243 1-128 26-35 50-66 99-117 EGSYDILTGYYVGVGRMDV (SEQ ID NO: 2171)I072E05 1760 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072E06 1761 135-242 156-166 182-188221-231 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO: 2161) I072F031762 135-242 156-166 182-188 221-231 1-119 26-35 50-66 99-108 GMGDHYGMDV(SEQ ID NO: 2161) I072F07 1763 141-251 163-176 192-198 231-240 1-12526-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072F11 1764140-247 161-171 187-193 226-236 1-124 26-35 50-66 99-113 DEYDILTGLLQGMDV(SEQ ID NO: 2883) I072G03 1765 141-248 162-172 188-194 227-237 1-12526-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072G04 1766137-247 159-171 187-193 226-236 1-121 26-35 50-68 101-110  RDILTGFYDS(SEQ ID NO: 2933) I072G05 1767 137-247 159-171 187-193 226-236 1-12126-35 50-66 99-110 GYRNDWYGAFEI (SEQ ID NO: 3079) I072G09 1768 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I072H03 1769 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I072H07 1770 137-247159-172 188-194 227-236 1-121 26-35 50-66 99-110 AGTSLMNYGMDV (SEQ IDNO: 3070) I073A02 1771 141-248 164-174 190-196 229-237 1-125 26-35 50-6699-114 GPYDILTGYYRDAFDI (SEQ ID NO: 2998) I073A03 1772 142-252 164-177193-199 232-241 1-126 26-35 50-66 99-115 THYDILTGYYTADAFDI (SEQ ID NO:3019) I073A04 1773 148-258 170-183 199-205 238-247 1-132 26-35 50-6699-121 VQMDSEYYDLLTGINVGPYYFDY (SEQ ID NO: 2132) I073A05 1774 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I073A06 1775 141-251 163-176 192-198 231-240 1-125 26-3550-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073A09 1776 141-251163-176 192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I073A10 1777 146-253 167-177 193-199 232-242 1-130 26-3550-66 99-119 GDFGDYDILTGYYPVYYGMDV (SEQ ID NO: 3082) I073A11 1778141-248 164-174 190-196 229-237 1-125 26-35 50-66 99-114SYYDILTGYYPFGMDV (SEQ ID NO: 3004) I073B02 1779 144-254 166-179 195-201234-243 1-128 26-35 50-66 99-117 DLWYYDILTGYYLDDAFDI (SEQ ID NO: 2999)I073B05 1780 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117DLWYYDILTGYYLDDAFDI (SEQ ID NO: 2999) I073B06 1781 139-246 160-170186-192 225-235 1-123 26-35 50-66 99-112 SRDLLLFPHYGMDV (SEQ ID NO:2133) I073B07 1782 138-248 160-173 189-195 228-237 1-122 26-35 50-6699-111 TRMDVLTRYYSDF (SEQ ID NO: 2750) I073B08 1783 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I073B11 1784 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073C01 1785 141-248 162-172188-194 227-237 1-125 26-35 50-66 99-114 GYHDTLTSYNYNWFDP (SEQ ID NO:3006) I073C02 1786 148-255 169-179 195-201 234-244 1-132 26-35 50-6699-121 AQMDSEYYDLLTGINVGPYYFDY (SEQ ID NO: 3076) I073C04 1787 141-252164-177 193-199 232-241 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQID NO: 2153) I073G07 1788 134-241 155-165 181-187 220-230 1-118 26-3550-66 99-107 GMGDHYMDV (SEQ ID NO: 3008) I073G08 1789 142-252 164-177193-199 232-241 1-126 26-35 50-66 99-115 EMGYDILTGYYLNYMDV (SEQ ID NO:2862) I073C09 1790 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 QHYDILTGYSQEPFDI (SEQ ID NO: 3022) I073C11 1791 146-256 168-181197-203 236-245 1-130 26-35 50-68 101-119  FNPTYDILTGYYIGGYFQH (SEQ IDNO: 2155) I073C12 1792 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073D01 1793 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I073D03 1794 135-245 157-169 185-191 224-234 1-119 26-35 50-6699-108 GMGDHYGMDV (SEQ ID NO: 2161) I073D06 1795 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I073D08 1796 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I073D10 1797 140-250 162-175191-197 230-239 1-124 26-35 50-68 101-113  QYYDILTGYELDI (SEQ ID NO:3073) I073D11 1798 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073E01 1799 148-258 170-183199-205 238-247 1-132 26-37 52-69 102-121  EGAHYDILTGHNYYHYGMDV (SEQ IDNO: 2747) I073E02 1800 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073E03 1801 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSLDGFDI (SEQ ID NO:3003) I073E05 1802 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 QHYDILTGYSQEPFDI (SEQ ID NO: 3022) I073E06 1803 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I073E08 1804 140-250 162-175 191-197 230-239 1-124 26-35 50-6699-113 ENYDFLTGYYGAFDI (SEQ ID NO: 2772) I073F01 1805 141-251 163-175191-197 230-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I073F02 1806 141-251 163-175 191-197 230-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073F03 1807 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I073F05 1808 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073F07 1809 141-251 163-175191-197 230-240 1-125 26-35 50-66 99-114 GEYDILTGYPYWYFDL (SEQ ID NO:3023) I073F09 1810 141-251 163-176 192-198 231-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDT (SEQ ID NO: 2153) I073F11 1811 141-251 163-176192-198 231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO:2153) I073F12 1812 141-251 163-175 191-197 230-240 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073G03 1813 143-253 165-178194-200 233-242 1-127 26-35 50-66 99-116 DGSYDILTGYYIDNYMDV (SEQ ID NO:2154) I073G04 1814 143-253 165-178 194-200 233-242 1-127 26-35 50-6598-116 GEGGYDILTGYLRGYGMDV (SEQ ID NO: 3037) I073G05 1815 135-245157-169 185-191 224-234 1-119 26-35 50-66 99-108 GMGDHYGMDV (SEQ ID NO:2161) I073G06 1816 141-248 162-172 188-194 227-237 1-125 26-35 50-6699-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073G07 1817 142-249 163-173189-195 228-238 1-126 26-35 50-66 99-115 GSYYDILTGISSLGMDV (SEQ ID NO:3063) I073G08 1818 139-246 160-170 186-192 225-235 1-123 26-35 50-6699-112 SRDLLLFPHYGMDV (SEQ ID NO: 2133) I073G09 1819 145-255 167-180196-202 235-244 1-129 26-35 50-66 99-118 DRGHYDILTGYYIEPSGFDY (SEQ IDNO: 3061) I073G10 1820 135-245 157-170 186-192 225-234 1-119 26-35 50-6699-108 GPGVIGNYDY (SEQ ID NO: 2749) I073G12 1821 142-252 164-177 193-199232-241 1-126 26-35 50-68 101-115  GGMIRAREDYYYMDV (SEQ ID NO: 3083)I073H01 1822 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073H03 1823 141-248 162-172 188-194227-237 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I073H05 1824 141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114ATYDPLTGYSFDGFDI (SEQ ID NO: 2153) I073H06 1825 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I073H07 1826 138-245 159-169 185-191 224-234 1-122 26-35 50-66 99-111TYYDILTGYYFDY (SEQ ID NO: 3056) I073H08 1827 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 ATYDPLTGYSFDGFDI (SEQ ID NO: 2153)I074A05 1828 143-255 166-179 195-201 234-244 1-127 26-35 50-66 99-116LPPYDMLTGYYVGGGMDV (SEQ ID NO: 3050) I074A06 1829 143-253 167-177193-199 232-242 1-127 26-35 50-66 99-116 AKPYTDFSRGSDADAFDV (SEQ ID NO:3065) I074B03 1830 133-242 156-166 182-188 221-231 1-117 26-35 50-6699-106 DQGRYLDL (SEQ ID NO: 2175) I074B11 1831 139-251 162-175 191-197230-240 1-123 26-35 50-66 99-112 RYGDPFYYYYYMNV (SEQ ID NO: 2755)I074C07 1832 140-251 163-175 191-197 230-240 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I074D03 1833 141-251 165-175 191-197230-240 1-125 26-35 50-66 99-114 GGYDILTQYPAEFFHP (SEQ ID NO: 2764)I074D04 1834 133-246 156-169 185-191 224-235 1-117 26-35 50-66 99-106DQGRYLDL (SEQ ID NO: 2175) I074D05 1835 143-253 167-177 193-199 232-2421-127 26-35 50-66 99-116 DRYYDILTKGDYYYGMDV (SEQ ID NO: 3060) I074D071836 150-262 173-186 202-208 241-251 1-134 26-35 50-66 99-123VQGETYYDILTGYWGPKRDLYGMDV (SEQ ID NO: 3069) I074D08 1837 140-251 163-175191-197 230-240 1-124 26-34 49-65 98-113 ELGLSIVVATTGALDM (SEQ ID NO:2980) I074D11 1838 138-249 161-174 190-196 229-238 1-122 26-35 50-6699-111 ESEGGDYTNPFGY (SEQ ID NO: 2991) I074E05 1839 133-245 156-169185-191 224-234 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175)I074E07 1840 140-251 163-175 191-197 230-240 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I074E09 1841 146-258 169-182 198-204237-247 1-130 26-35 50-68 101-119  DPGNYDILTGYYYYYGMDV (SEQ ID NO: 2935)I074E11 1842 137-244 160-170 186-192 225-233 1-121 26-35 50-66 99-110VRLPHHHYFMAV (SEQ ID NO: 3075) I074H05 1843 142-254 166-178 194-200233-243 1-126 26-35 50-66 99-115 ESSITVNPPYYFYGMDV (SEQ ID NO: 3025)I075A03 1844 133-242 158-168 184-190 223-231 1-117 26-35 50-66 99-106DQGRYLDL (SEQ ID NO: 2175) I075A10 1845 133-244 157-169 185-191 224-2331-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175) I075B07 1846 143-254166-178 194-200 233-243 1-127 26-35 50-66 99-116 SPEGDYQPLSSNYNWLDP (SEQID NO: 3011) I075D11 1847 133-246 156-169 185-191 224-235 1-117 26-3651-66 99-106 GKEGYNDN (SEQ ID NO: 3089) I075D12 1848 143-253 167-177193-199 232-242 1-127 26-35 50-66 99-116 GSGYDLLTGYFTGSPLDY (SEQ ID NO:2766) I075G02 1849 143-255 166-179 195-201 234-244 1-127 26-35 50-6699-116 SPEGDYQPLSSNYNWLDP (SEQ ID NO: 3011) I075G09 1850 142-253 165-177193-199 232-242 1-126 26-35 50-66 99-115 MGHYDILTGYRHYGMDV (SEQ ID NO:2831) I075G10 1851 138-250 162-174 190-196 229-239 1-122 26-35 50-6699-111 GNYDILTGYPHDL (SEQ ID NO: 3086) I075H05 1852 141-252 164-176192-198 231-241 1-125 26-35 50-66 99-114 SYYDILTGYYHTPLDY (SEQ ID NO:2853) I075H07 1853 143-253 167-177 193-199 232-242 1-127 26-35 50-6699-116 GSGYDLLTGYFTGSPLDY (SEQ ID NO: 2766) I076A11 1854 141-254 164-177193-199 232-243 1-125 26-35 50-66 99-114 DDRDILTNYYLEYFQH (SEQ ID NO:2868) I076A12 1855 143-256 166-178 194-200 233-245 1-127 26-35 50-6699-116 GSGYDVLTGYFTGSPLDY (SEQ ID NO: 3057) I076B06 1856 140-249 164-174190-196 229-238 1-124 26-35 50-66 99-113 GRYDILTGYFTSFDY (SEQ ID NO:3066) I076B10 1857 141-254 164-177 193-199 232-243 1-125 26-35 50-6699-114 DDRDILTNYYLEYFQH (SEQ ID NO: 2868) I076B12 1858 143-253 167-177193-199 232-242 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO:2800) I076C06 1859 142-253 165-177 193-199 232-242 1-126 26-35 50-6699-115 MGHYDILTGYRHYGMDV (SEQ ID NO: 2831) I076C11 1860 133-245 156-168184-190 223-234 1-117 26-35 50-66 99-106 DQGRYLDL (SEQ ID NO: 2175)I076D06 1861 140-252 163-176 192-198 231-241 1-124 26-34 49-65 98-113ELGLSIVGATTGALDM (SEQ ID NO: 2174) I076E05 1862 143-255 166-179 195-201234-244 1-127 26-35 50-66 99-116 GTGYDILTGYYMGSAFDQ (SEQ ID NO: 2800)I076E08 1863 133-243 157-167 183-189 222-232 1-117 26-35 50-66 99-106DQGRYLDL (SEQ ID NO: 2175) I076F06 1864 133-245 156-169 185-191 224-2341-117 26-36 51-66 99-106 RDVQGAPY (SEQ ID NO: 3088) I076G01 1865 143-254166-178 194-200 233-243 1-127 26-35 50-66 99-116 VEGVYDILTGYSFDAFDI (SEQID NO: 3078) I076H01 1866 144-254 168-178 194-200 233-243 1-128 26-3550-66 99-117 EQGYDILTGYYPEGGWFDP (SEQ ID NO: 2834) I076H03 1867 140-250164-174 190-196 229-239 1-124 26-34 49-65 98-113 ELGLSIVGATTGALDM (SEQID NO: 2174) I077B05 1868 147-257 169-182 198-204 237-246 1-131 26-3752-69 102-120  DKSYYDILTGYYYYYGMDV (SEQ ID NO: 3052) I077C10 1869141-251 163-176 192-198 231-240 1-125 26-35 50-66 99-114MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I077D01 1870 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179)I077D04 1871 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I077D11 1872 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179)I077D12 1873 140-247 161-171 187-193 226-236 1-124 26-35 50-66 99-113EKYDILTGYYDAFDI (SEQ ID NO: 3046) I077E01 1874 142-252 164-177 193-199232-241 1-126 26-35 50-66 99-115 EMGYDILTGYYLNYMDV (SEQ ID NO: 2862)I077E03 1875 142-252 164-177 193-199 232-241 1-126 26-35 50-66 99-115EMGYDILTGYYLNYMDV (SEQ ID NO: 2862) I077E08 1876 141-248 164-174 190-196229-237 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179)I077F05 1877 141-248 162-172 188-194 227-237 1-125 26-35 50-66 99-114MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I077G06 1878 141-251 163-176 192-198231-240 1-125 26-35 50-66 99-114 MEYDILTGYYGGYFDY (SEQ ID NO: 2179)I077H02 1879 141-248 164-174 190-196 229-237 1-125 26-35 50-66 99-114MEYDILTGYYGGYFDY (SEQ ID NO: 2179) I078B05 1880 143-253 165-178 194-200233-242 1-127 26-35 50-66 99-116 ESHYDILTGYYSNPSFDI (SEQ ID NO: 2994)I079E02 1881 137-244 160-170 186-192 225-233 1-121 26-35 50-66 99-110DSGSYYYDAFDI (SEQ ID NO: 2194) I079F11 1882 132-239 155-165 181-187220-228 1-116 26-35 50-66 99-105 TGSGFDY (SEQ ID NO: 2192) I082G02 1883136-243 159-169 185-191 224-232 1-120 26-35 50-66 99-109 DGYRTNDALDI(SEQ ID NO: 2191) I082H08 1884 131-242 154-167 183-189 222-231 1-11526-35 50-66 99-104 DWDMDV (SEQ ID NO: 2193) I099D03 1885 136-247 159-172188-194 227-236 1-120 26-35 50-66 99-109 DNGGGTIGFDY (SEQ ID NO: 2195)I079B05 1886 130-240 152-165 181-187 220-229 1-114 26-35 50-66 99-103FVLDY (SEQ ID NO: 2210) I079B12 1887 134-241 157-167 183-189 222-2301-118 26-35 50-66 99-107 WTSSGAFDI (SEQ ID NO: 2205) I079C01 1888131-241 153-166 182-188 221-230 1-115 26-35 50-66 99-104 DWDMDV (SEQ IDNO: 2193) I079F06 1889 134-241 157-167 183-189 222-230 1-118 26-35 50-6699-107 DNLHAAFDI (SEQ ID NO: 2202) I079F08 1890 138-248 160-172 188-194227-237 1-122 26-35 50-66 99-111 YYYHSSGSDAFDI (SEQ ID NO: 2206) I080A031891 138-249 161-173 189-195 228-238 1-122 26-35 50-66 99-111VGIKAAAVDNFEY (SEQ ID NO: 2197) I080A08 1892 135-247 158-171 187-193226-236 1-119 26-35 50-66 99-108 VHSTGYAFEN (SEQ ID NO: 2200) I080B011893 142-254 166-178 194-200 233-243 1-126 26-35 50-66 99-115EYSGYHYVEGGSYAMDV (SEQ ID NO: 2201) I080D03 1894 138-249 161-173 189-195228-238 1-122 26-35 50-66 99-111 VGIKAAAVDNFEY (SEQ ID NO: 2197) I080E051895 141-253 164-177 193-199 232-242 1-125 26-35 50-66 99-114EGGGDAYDVAPYYFDY (SEQ ID NO: 2204) I080G07 1896 136-245 161-172 188-194227-234 1-120 26-35 50-66 99-109 EGPGYYYGMDV (SEQ ID NO: 2209) I080G091897 136-249 159-172 188-194 227-238 1-120 26-35 50-66 99-109DNGGGTIGFDY (SEQ ID NO: 2195) I082A05 1898 131-240 153-165 181-187220-229 1-115 26-35 50-66 99-104 DLDFDY (SEQ ID NO: 2208) I082B08 1899137-247 159-171 187-193 226-236 1-121 26-35 50-66 99-110 DLGIAGTIYFDY(SEQ ID NO: 2207) I082C03 1900 138-245 161-171 187-193 226-234 1-12226-35 50-66 99-111 DASRDIVVLPLAI (SEQ ID NO: 2198) I082D07 1901 134-241157-167 183-189 222-230 1-118 26-35 50-66 99-107 WTSSGAFDI (SEQ ID NO:2205) I082G01 1902 138-245 161-171 187-193 226-234 1-122 26-35 50-6699-111 DRGSGWPNWYFDL (SEQ ID NO: 2212) I083B12 1903 137-247 161-171187-193 226-236 1-121 26-35 50-66 99-110 ESGAGGYYYDDY (SEQ ID NO: 2196)I083G03 1904 138-249 161-173 189-195 228-238 1-122 26-35 50-66 99-111VGIKAAAVDNFEY (SEQ ID NO: 2197) I084A01 1905 130-240 152-164 180-186219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I084B02 1906130-237 153-163 179-185 218-226 1-114 26-35 50-66 99-103 DTTDY (SEQ IDNO: 2203) I084C04 1907 131-238 152-162 178-184 217-227 1-115 25-34 49-6598-104 NLWGLDY (SEQ ID NO: 2199) I084C11 1908 134-244 156-169 185-191224-233 1-118 26-35 50-66 99-107 GNAWGAFDI (SEQ ID NO: 2211) I079A011909 134-243 156-168 184-190 223-232 1-118 26-35 50-66 99-107 EGVAAGEDY(SEQ ID NO: 3123) I079A03 1910 134-244 156-169 185-191 224-233 1-11826-35 50-66 99-107 GGMDWDFDY (SEQ ID NO: 3183) I079A04 1911 134-241155-165 181-187 220-230 1-118 26-35 50-66 99-107 VDSSGYAYY (SEQ ID NO:3213) I079A06 1912 133-240 154-164 180-186 219-229 1-117 26-35 50-6699-106 DAAVTAEG (SEQ ID NO: 3142) I079A07 1913 136-246 158-170 186-192225-235 1-120 26-35 50-66 99-109 GSNYSPDAFDI (SEQ ID NO: 3112) I079A101914 148-255 169-179 195-201 234-244 1-132 26-35 50-68 101-121 LPPDLRYCDGGICPGFDWLGP (SEQ ID NO: 3163) I079A11 1915 135-242 158-168184-190 223-231 1-119 26-35 50-66 99-108 GPSYYYYMAV (SEQ ID NO: 3114)I079B02 1916 134-243 156-168 184-190 223-232 1-118 26-35 50-66 99-107EGVAAGEDY (SEQ ID NO: 3123) I079B03 1917 136-246 158-170 186-192 225-2351-120 26-35 50-66 99-109 GSNYSPDAFDI (SEQ ID NO: 3112) I079B04 1918130-240 152-165 181-187 220-229 1-114 26-35 50-66 99-103 LLSDY (SEQ IDNO: 3168) I079B07 1919 138-245 159-169 185-191 224-234 1-122 26-35 50-6699-111 DLSGSYFSRYFDY (SEQ ID NO: 3193) I079B09 1920 139-246 162-172188-194 227-235 1-123 26-35 50-66 99-112 VEWEDIVVGSAFDI (SEQ ID NO:3128) I079C02 1921 144-251 167-177 193-199 232-240 1-128 26-35 50-6699-117 VTSLYSSSSGGYYYYGMDV (SEQ ID NO: 3145) I079C04 1922 132-239155-165 181-187 220-228 1-116 26-35 50-66 99-105 GWRGVDY (SEQ ID NO:3195) I079C05 1923 140-247 163-173 189-195 228-236 1-124 26-35 50-6699-113 AGGNPRSGSLVYFDY (SEQ ID NO: 3225) I079C07 1924 137-244 158-168184-190 223-233 1-121 26-35 50-66 99-110 GLDVYAIYGLDV (SEQ ID NO: 3176)I079D01 1925 144-254 166-179 195-201 234-243 1-128 26-35 50-66 99-117EVRNYDLLTRSYLAGPLDN (SEQ ID NO: 2751) I079D02 1926 135-245 157-169185-191 224-234 1-119 26-35 50-66 99-108 EIGWEGAFDI (SEQ ID NO: 3178)I079D04 1927 133-243 155-167 183-189 222-232 1-117 26-35 50-66 99-106VRPGLMDV (SEQ ID NO: 3132) I079D06 1928 137-247 159-171 187-193 226-2361-121 26-35 50-66 99-110 EAYTSSWAEFDF (SEQ ID NO: 3190) I079D07 1929136-243 157-167 183-189 222-232 1-120 26-35 50-66 99-109 NITPLAMVGDF(SEQ ID NO: 3146) I079D08 1930 130-240 152-165 181-187 220-229 1-11426-35 50-66 99-103 LIEDF (SEQ ID NO: 3161) I079D09 1931 131-238 152-162178-184 217-227 1-115 26-35 50-66 99-104 DSGSPD (SEQ ID NO: 3108)I079D11 1932 134-241 157-167 183-189 222-230 1-118 26-35 50-66 99-107EGVAAGEDY (SEQ ID NO: 3123) I079E06 1933 136-244 158-168 184-190 223-2331-120 26-35 50-66 99-109 EKRGSRRVFDI (SEQ ID NO: 3093) I079E08 1934137-247 159-171 187-193 226-236 1-121 26-35 50-66 99-110 EAYASSWAEFDF(SEQ ID NO: 3189) I079E11 1935 136-243 159-169 185-191 224-232 1-12026-35 50-66 99-109 PYGSGSYAFDI (SEQ ID NO: 3185) I079E12 1936 143-253165-177 193-199 232-242 1-127 26-35 50-66 99-116 ARDYYDSSGYYVPDAFDI (SEQID NO: 3107) I079F01 1937 133-241 154-164 180-186 219-230 1-117 26-3550-66 99-106 GHFYGMDV (SEQ ID NO: 3098) I079F02 1938 148-253 169-179195-201 234-242 1-132 26-35 50-68 101-121  LPPDLRYGDGGMCSGFDWLGP (SEQ IDNO: 3219) I079F03 1939 140-247 161-171 187-193 226-236 1-124 26-35 50-6699-113 ESLLTEEYCGSDCYS (SEQ ID NO: 3115) I079F04 1940 136-243 157-167183-189 222-232 1-120 26-35 50-66 99-109 NSAPPAPSMDV (SEQ ID NO: 3099)I079F09 1941 130-237 151-161 177-183 216-226 1-114 26-35 50-66 99-103RYYDY (SEQ ID NO: 3139) I079F10 1942 136-243 157-167 183-189 222-2321-120 26-35 50-66 99-109 NITPLAMVGDF (SEQ ID NO: 3146) I079F12 1943136-243 159-169 185-191 224-232 1-120 26-35 50-66 99-109 ADYSNDYYMDV(SEQ ID NO: 3166) I079G02 1944 136-243 157-167 183-189 222-232 1-12026-35 50-66 99-109 NITPLAMVGDF (SEQ ID NO: 3146) I079G05 1945 136-243159-169 185-191 224-232 1-120 26-35 50-66 99-109 FPLESYYYMDV (SEQ ID NO:3124) I079G06 1946 135-245 157-170 186-192 225-234 1-119 26-35 50-6699-108 GNSFGRTLDY (SEQ ID NO: 3158) I079H05 1947 136-243 157-167 183-189222-232 1-120 26-35 50-66 99-109 DVPPPDGYLEV (SEQ ID NO: 3192) I079H061948 134-241 157-167 183-189 222-230 1-118 26-35 50-66 99-107 ASYPVPFDY(SEQ ID NO: 3171) I080A01 1949 131-242 154-166 182-188 221-231 1-11526-35 50-66 99-104 GGWLDD (SEQ ID NO: 3210) I080A02 1950 133-245 156-169185-191 224-234 1-117 26-35 50-66 99-106 EHSSSFDY (SEQ ID NO: 3111)I080A05 1951 141-253 164-177 193-199 232-242 1-125 26-35 50-66 99-114EGEGDGYNVAPYYFDY (SEQ ID NO: 3160) I080A06 1952 141-250 166-176 192-198231-239 1-125 26-35 50-66 99-114 EAGGSGSYHFSFPFDY (SEQ ID NO: 3188)I080A07 1953 135-247 158-171 187-193 226-236 1-119 26-35 50-66 99-108TGIWGYYFDY (SEQ ID NO: 3175) I080A10 1954 141-252 164-176 192-198231-241 1-125 26-35 50-66 99-114 DGNLNYDGSTDYGMDV (SEQ ID NO: 3140)I080B02 1955 138-248 162-172 188-194 227-237 1-122 26-35 50-66 99-111LGRNYTSSWSLDY (SEQ ID NO: 3181) I080B03 1956 138-249 161-173 189-195228-238 1-122 26-35 50-66 99-111 VVGGYSSTLGTDV (SEQ ID NO: 3096) I080B051957 137-249 161-173 189-195 228-238 1-121 26-35 50-66 99-110LGVARGREAFDL (SEQ ID NO: 3206) I080B06 1958 142-254 165-177 193-199232-243 1-126 26-37 52-69 102-115  AVRSPGYYYYYMDV (SEQ ID NO: 3125)I080B07 1959 133-243 157-167 183-189 222-232 1-117 26-35 50-66 99-106GRKPLFDY (SEQ ID NO: 3141) I080B08 1960 136-248 159-172 188-194 227-2371-120 26-37 52-67 100-109  KQRREKYFDY (SEQ ID NO: 3100) I080B09 1961142-254 165-178 194-200 233-243 1-126 26-35 50-66 99-115EKAIIETTSGEADPFDI (SEQ ID NO: 3151) I080B10 1962 138-249 161-173 189-195228-238 1-122 26-37 52-67 100-111  RPALRSLWYFDL (SEQ ID NO: 3102)I080B11 1963 137-248 160-172 188-194 227-237 1-121 26-35 50-68 101-110 LHCTGGSCGF (SEQ ID NO: 3186) I080B12 1964 139-253 164-179 195-201234-242 1-123 26-35 50-66 99-112 NPYYYDSSEGFFDY (SEQ ID NO: 3109)I080C03 1965 138-248 162-172 188-194 227-237 1-122 26-35 50-66 99-111SGRQAYYYYGMDV (SEQ ID NO: 3091) I080C06 1966 144-254 168-178 194-200233-243 1-128 26-36 51-66 99-117 DYYDGSSYSSGDYYYYMDV (SEQ ID NO: 3227)I080C07 1967 144-256 167-180 196-202 235-245 1-128 26-35 50-66 99-117DSDLVVIPTAIQGRYYFDN (SEQ ID NO: 3113) I080C08 1968 137-249 160-173189-195 228-238 1-121 26-35 50-66 99-110 GKRYSYGWYFDI (SEQ ID NO: 3130)I080C10 1969 131-243 154-167 183-189 222-232 1-115 26-35 50-66 99-104DTPLDP (SEQ ID NO: 3094) I080C11 1970 137-249 160-173 189-195 228-2381-121 26-35 50-66 99-110 EGDPTDNDAFDV (SEQ ID NO: 3155) I080C12 1971138-249 161-173 189-195 228-238 1-122 26-35 50-66 99-111 DGPTYARPYYLDH(SEQ ID NO: 3153) I080D01 1972 136-245 161-171 187-193 226-234 1-12026-35 50-66 99-109 DGTKYDWGFDY (SEQ ID NO: 3220) I080D02 1973 141-254164-177 193-199 232-243 1-125 26-35 50-66 99-114 ETFSHCSGGSCYPFDY (SEQID NO: 3212) I080D04 1974 138-248 162-172 188-194 227-237 1-122 26-3550-66 99-111 SGRQAYYYYGMDV (SEQ ID NO: 3091) I080D05 1975 136-246160-170 186-192 225-235 1-120 26-35 50-66 99-109 EFFGYVYLTDY (SEQ ID NO:3165) I080D08 1976 137-248 160-172 188-194 227-237 1-121 26-35 50-68101-110  LHCTGGSCGF (SEQ ID NO: 3186) I080D09 1977 138-250 161-174190-196 229-239 1-122 26-35 50-66 99-111 VDYTDYEMGAFEI (SEQ ID NO: 3187)I080D11 1978 135-247 158-171 187-193 226-236 1-119 26-35 50-66 99-108VGNFGYYFEY (SEQ ID NO: 3196) I080D12 1979 135-245 159-169 185-191224-234 1-119 26-35 50-68 101-108  SSRNGGDY (SEQ ID NO: 3214) I080E011980 136-246 160-170 186-192 225-235 1-120 26-35 50-66 99-109DLSRVAGRFDY (SEQ ID NO: 3164) I080E04 1981 136-247 159-171 187-193226-236 1-120 26-37 52-67 100-109  HDVYGDLFDY (SEQ ID NO: 3211) I080E061982 137-248 160-172 188-194 227-237 1-121 26-35 50-68 101-110 LHCSGGSCGF (SEQ ID NO: 3221) I080E07 1983 142-254 165-178 194-200233-243 1-126 26-35 50-66 99-115 EGSIVGATLTINDAFDI (SEQ ID NO: 3150)I080E08 1984 137-249 160-173 189-195 228-238 1-121 26-35 50-66 99-110GKRYSYGWYFDI (SEQ ID NO: 3130) I080E12 1985 130-242 154-166 182-188221-231 1-114 26-35 50-66 99-103 DPFDY (SEQ ID NO: 3134) I080F04 1986138-249 161-173 189-195 228-238 1-122 26-35 50-66 99-111 DGPTYARPYYLDH(SEQ ID NO: 3153) I080F05 1987 142-253 165-177 193-199 232-242 1-12626-35 50-66 99-115 ESSGTLGEFSLELPFDY (SEQ ID NO: 3203) I080F06 1988138-248 162-172 188-194 227-237 1-122 26-35 50-66 99-111 LGRNYTSSWSLDY(SEQ ID NO: 3181) I080F08 1989 130-240 154-164 180-186 219-229 1-11426-35 50-66 99-103 NAFDY (SEQ ID NO: 3121) I080G03 1990 140-250 164-174190-196 229-239 1-124 26-36 51-66 99-113 GRGYSSSSSVYGMDI (SEQ ID NO:3095) I080G04 1991 131-244 156-171 187-193 226-233 1-115 26-35 50-6699-104 VHSSGS (SEQ ID NO: 3216) I080G10 1992 143-252 167-177 193-199232-241 1-127 26-35 50-66 99-116 KRGDFGVIRLHHYYGMDV (SEQ ID NO: 3136)I080G11 1993 136-247 159-171 187-193 226-236 1-120 26-37 52-67 100-109 HDVYGDLFDS (SEQ ID NO: 3205) I080H01 1994 140-252 164-176 192-198231-241 1-124 26-37 52-67 100-113  LRPDADYGDYGFDY (SEQ ID NO: 3218)I080H02 1995 139-248 162-172 188-194 227-237 1-123 26-35 50-66 99-112TSERGTYRQWDFDN (SEQ ID NO: 3204) I080H03 1996 135-246 158-170 186-192225-235 1-119 26-35 50-66 99-108 EAGEVAAIDY (SEQ ID NO: 3180) I080H041997 137-249 160-173 189-195 228-238 1-121 26-35 50-66 99-110GKRYSYGWYFDI (SEQ ID NO: 3130) I080H05 1998 136-247 159-171 187-193226-236 1-120 26-37 52-67 100-109  HDVYGDLFDS (SEQ ID NO: 3205) I080H061999 137-249 160-173 189-195 228-238 1-121 26-35 50-66 99-110GKRYSYGWYFDV (SEQ ID NO: 3217) I080H07 2000 137-248 160-172 188-194227-237 1-121 26-35 50-68 101-110  LHCTGGSCGF (SEQ ID NO: 3186) I080H082001 138-251 162-175 191-197 230-240 1-122 26-35 50-66 99-111ERGGRDGDYALDF (SEQ ID NO: 3148) I080H09 2002 139-249 163-173 189-195228-238 1-123 26-36 51-66 99-112 RTPDHNGDSGPPDY (SEQ ID NO: 3215)I081A01 2003 130-237 153-163 179-185 218-226 1-114 26-35 50-66 99-103DTTDY (SEQ ID NO: 2203) I081A03 2004 135-245 157-170 186-192 225-2341-119 26-35 50-66 99-108 ESLTGGAFDI (SEQ ID NO: 3117) I081A04 2005130-237 153-163 179-185 218-226 1-114 26-35 50-66 99-103 DTTDY (SEQ IDNO: 2203) I081A06 2006 130-237 151-161 177-183 216-226 1-114 26-35 50-6699-103 DTTDY (SEQ ID NO: 2203) I081A08 2007 130-240 152-164 180-186219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081A09 2008134-241 155-165 181-187 220-230 1-118 26-35 50-66 99-107 GAGSRYFDL (SEQID NO: 3118) I081A10 2009 133-243 155-168 184-190 223-232 1-117 26-3550-66 99-106 GGDRAFDI (SEQ ID NO: 3119) I081B01 2010 130-236 151-161177-183 216-225 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081B042011 134-244 156-169 185-191 224-233 1-118 26-35 50-66 99-107 GNAWGAFDI(SEQ ID NO: 2211) I081B05 2012 133-243 155-168 184-190 223-232 1-11726-35 50-66 99-106 GGDRAFDI (SEQ ID NO: 3119) I081B06 2013 133-240154-164 180-186 219-229 1-117 26-35 50-66 99-106 VKRYYFDY (SEQ ID NO:3179) I081B07 2014 136-243 157-167 183-189 222-232 1-120 26-35 50-6699-109 ELTGANDAFDI (SEQ ID NO: 3104) I081B08 2015 132-239 153-163179-185 218-228 1-116 26-35 50-66 99-105 RRYALDY (SEQ ID NO: 2920)I081B09 2016 130-240 152-164 180-186 219-229 1-114 26-35 50-66 99-103DTTDY (SEQ ID NO: 2203) I081B10 2017 130-237 153-163 179-185 218-2261-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081B11 2018 132-239153-163 179-185 218-228 1-116 26-35 50-66 99-105 GFALYKD (SEQ ID NO:3169) I081C07 2019 130-237 153-163 179-185 218-226 1-114 26-35 50-6699-103 DTTDY (SEQ ID NO: 2203) I081C08 2020 130-237 153-163 179-185218-226 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081D04 2021135-242 156-166 182-188 221-231 1-119 26-35 50-66 99-108 EDLTGDAFDI (SEQID NO: 3103) I081D06 2022 132-239 153-163 179-185 218-228 1-116 26-3550-66 99-105 GDAYFDY (SEQ ID NO: 3147) I081D08 2023 132-239 153-163179-185 218-228 1-116 26-35 50-66 99-105 GDAYFDY (SEQ ID NO: 3147)I081D09 2024 130-238 152-162 178-184 217-227 1-114 26-35 50-66 99-103DTTDY (SEQ ID NO: 2203) I081D10 2025 130-240 152-164 180-186 219-2291-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081D11 2026 134-244156-169 185-191 224-233 1-118 26-35 50-66 99-107 EGLLDAFDI (SEQ ID NO:3200) I081D12 2027 130-237 153-163 179-185 218-226 1-114 26-35 50-6699-103 DTTDY (SEQ ID NO: 2203) I081E02 2028 130-237 153-163 179-185218-226 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081E03 2029130-240 152-164 180-186 219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ IDNO: 2203) I081E05 2030 130-240 152-164 180-186 219-229 1-114 26-35 50-6699-103 DTTDY (SEQ ID NO: 2203) I081E06 2031 134-241 155-165 181-187220-230 1-118 26-35 50-66 99-107 VGYGGKGDY (SEQ ID NO: 3137) I081E072032 134-241 155-165 181-187 220-230 1-118 26-35 50-66 99-107 GAGSRYFDL(SEQ ID NO: 3118) I081E10 2033 142-249 163-173 189-195 228-238 1-12626-35 50-66 99-115 GLAPIVDGGMTNDAFDI (SEQ ID NO: 3184) I081F01 2034130-239 152-164 180-186 219-228 1-114 26-35 50-66 99-103 DTTDY (SEQ IDNO: 2203) I081F04 2035 132-239 153-163 179-185 218-228 1-116 26-35 50-6699-105 RLIRKAR (SEQ ID NO: 3170) I081F05 2036 130-237 151-161 177-183216-226 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081F06 2037134-244 156-169 185-191 224-233 1-118 26-35 50-66 99-107 ERGNQAFDI (SEQID NO: 3156) I081F07 2038 132-239 153-163 179-185 218-228 1-116 26-3550-66 99-105 RRYALDY (SEQ ID NO: 2920) I081F11 2039 130-237 151-161177-183 216-226 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081G012040 130-237 153-163 179-185 218-226 1-114 26-35 50-66 99-103 DTTDY (SEQID NO: 2203) I081G04 2041 130-240 152-164 180-186 219-229 1-114 26-3550-66 99-103 DTTDY (SEQ ID NO: 2203) I081G06 2042 135-245 157-170186-192 225-234 1-119 26-35 50-66 99-108 SRSPYDAFDI (SEQ ID NO: 3097)I081G10 2043 130-237 153-163 179-185 218-226 1-114 26-35 50-66 99-103DTTDY (SEQ ID NO: 2203) I081H02 2044 130-240 152-164 180-186 219-2291-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I081H03 2045 130-240152-164 180-186 219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203)I081H04 2046 135-242 156-166 182-188 221-231 1-119 26-35 50-66 99-108SNWGGDAFDI (SEQ ID NO: 3202) I081H06 2047 130-240 152-165 181-187220-229 1-114 26-35 50-66 99-103 LAFDI (SEQ ID NO: 3174) I081H08 2048130-240 152-164 180-186 219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ IDNO: 2203) I082A02 2049 139-249 161-173 189-195 228-238 1-123 26-35 50-6699-112 PAASSRGPKDAFDI (SEQ ID NO: 3129) I082A04 2050 130-240 152-165181-187 220-229 1-114 26-35 50-66 99-103 LSGDS (SEQ ID NO: 3122) I082A082051 134-243 156-168 184-190 223-232 1-118 26-35 50-66 99-107 EGVAAGEDY(SEQ ID NO: 3123) I082A11 2052 130-240 152-165 181-187 220-229 1-11426-35 50-66 99-103 FVLDY (SEQ ID NO: 2210) I082B06 2053 131-238 154-164180-186 219-227 1-115 26-35 50-66 99-104 GNGKDV (SEQ ID NO: 3135)I082B09 2054 134-241 157-167 183-189 222-230 1-118 26-35 50-66 99-107EGVAAGEDY (SEQ ID NO: 3123) I082B12 2055 131-241 153-166 182-188 221-2301-115 26-35 50-66 99-104 DLDFDY (SEQ ID NO: 2208) I082C01 2056 136-243157-167 183-189 222-232 1-120 26-35 50-66 99-109 VNDIVVVDMDV (SEQ ID NO:3143) I082C05 2057 136-243 157-167 183-189 222-232 1-120 26-35 50-6699-109 EKRGSRRVFDI (SEQ ID NO: 3093) I082C08 2058 137-244 158-168184-190 223-233 1-121 26-35 50-66 99-110 LSNRNDNLRLDY (SEQ ID NO: 3106)I082D02 2059 130-240 152-165 181-187 220-229 1-114 26-35 50-66 99-103FVLDY (SEQ ID NO: 2210) I082E05 2060 134-241 155-165 181-187 220-2301-118 26-35 50-66 99-107 TWATNTFDM (SEQ ID NO: 3152) I082E06 2061130-240 152-165 181-187 220-229 1-114 26-35 50-66 99-103 FDLDY (SEQ IDNO: 3167) I082E07 2062 139-246 162-172 188-194 227-235 1-123 26-35 50-6699-112 VEWEDIVVGSAFDI (SEQ ID NO: 3128) I082F11 2063 136-243 159-169185-191 224-232 1-120 26-35 50-66 99-109 GGDMTTVTTDY (SEQ ID NO: 3177)I082G07 2064 136-243 159-169 185-191 224-232 1-120 26-35 50-66 99-109ADYSNDYYMDV (SEQ ID NO: 3166) I082G10 2065 134-249 160-173 189-195228-238 1-118 26-35 50-66 99-107 EGVAAGEDY (SEQ ID NO: 3123) I082G112066 143-250 164-174 190-196 229-239 1-127 26-35 50-66 99-116GPIYYFDGSAYEGYYFDY (SEQ ID NO: 3222) I082H04 2067 132-238 153-163179-185 218-227 1-116 26-35 50-65 98-105 MNADAFEI (SEQ ID NO: 3223)I082H09 2068 139-246 160-170 186-192 225-235 1-123 26-35 50-66 99-112PAASSRGPKDAFDI (SEQ ID NO: 3129) I083A06 2069 136-244 159-169 185-191224-233 1-120 26-35 50-66 99-109 DSRPTNRAFHY (SEQ ID NO: 3110) I083A092070 137-248 160-172 188-194 227-237 1-121 26-35 50-68 101-110 LHCTGGSCGF (SEQ ID NO: 3186) I083A11 2071 135-248 158-171 187-193226-237 1-119 26-35 50-66 99-108 VRDDSAGFDY (SEQ ID NO: 3173) I083B032072 137-247 161-171 187-193 226-236 1-121 26-35 50-66 99-110VLVRGQYRGMDL (SEQ ID NO: 3138) I083B05 2073 138-250 161-174 190-196229-239 1-122 26-35 50-66 99-111 VDYTDYEMGAFDL (SEQ ID NO: 3172) I083B062074 138-250 161-174 190-196 229-239 1-122 26-35 50-66 99-111DRIAAAGGDAFDI (SEQ ID NO: 3194) I083B10 2075 137-246 162-172 188-194227-235 1-121 26-35 50-66 99-110 DLYKNGYALFDS (SEQ ID NO: 3197) I083C012076 135-247 158-171 187-193 226-236 1-119 26-35 50-66 99-108 DEYSSLYMDV(SEQ ID NO: 3201) I083C02 2077 135-246 158-171 187-193 226-235 1-11926-35 50-66 99-108 FGAGRLYDDY (SEQ ID NO: 3224) I083C07 2078 136-249159-172 188-194 227-238 1-120 26-35 50-66 99-109 DNGGGTIGFDY (SEQ ID NO:2195) I083C12 2079 135-246 158-171 187-193 226-235 1-119 26-35 50-6699-108 DQGIETANDY (SEQ ID NO: 3207) I083D04 2080 145-256 168-181 197-203236-245 1-129 26-35 50-66 99-118 DILPDYDFWNPNEDASSLDT (SEQ ID NO: 3133)I083D07 2081 148-262 173-188 204-210 243-251 1-132 26-35 50-66 99-121DFQMVRGVFIANPPIYNYYGMDV (SEQ ID NO: 3154) I083D08 2082 142-254 165-178194-200 233-243 1-126 26-35 50-66 99-115 DADEGLVEAETTNWFDS (SEQ ID NO:3126) I083D10 2083 146-258 169-181 197-203 236-247 1-130 26-37 52-69102-119  ATKSYDILTRMYYYHMDV (SEQ ID NO: 2748) I083D12 2084 132-242156-166 182-188 221-231 1-116 26-35 50-66 99-105 DRTRMDV (SEQ ID NO:3182) I083E02 2085 138-249 161-173 189-195 228-238 1-122 26-35 50-6699-111 VGIKAAAVDNFEY (SEQ ID NO: 2197) I083E03 2086 135-248 158-171187-193 226-237 1-119 26-35 50-66 99-108 DEIYNDAFDY (SEQ ID NO: 3105)I083E04 2087 143-255 166-179 195-201 234-244 1-127 26-35 50-66 99-116DGDISDSPINNQNYAMDI (SEQ ID NO: 3101) I083E08 2088 138-248 162-172188-194 227-237 1-122 26-35 50-66 99-111 RGGTSENYSGMDV (SEQ ID NO: 3209)I083E12 2089 134-245 157-170 186-192 225-234 1-118 26-35 50-66 99-107DYPHNAFDI (SEQ ID NO: 3127) I083F02 2090 145-258 168-181 197-203 236-2471-129 26-35 50-66 99-118 DVRSDRFWSGGYFHYSGMDV (SEQ ID NO: 3131) I083F042091 137-248 160-172 188-194 227-237 1-121 26-35 50-66 99-110STLEVGATDFDY (SEQ ID NO: 3199) I083F06 2092 134-247 157-170 186-192225-236 1-118 26-35 50-66 99-107 SDDWGAYHI (SEQ ID NO: 3198) I083F082093 138-250 161-174 190-196 229-239 1-122 26-35 50-66 99-111ERGGRDGDYALDF (SEQ ID NO: 3148) I083F11 2094 136-248 159-172 188-194227-237 1-120 26-35 50-66 99-109 ELVGAPGGFDP (SEQ ID NO: 3191) I083G042095 138-250 161-174 190-196 229-239 1-122 26-35 50-66 99-111VDYTDYEMGAFDL (SEQ ID NO: 3172) I083G05 2096 137-249 161-173 189-195228-238 1-121 26-35 50-68 101-110  SVAGRGNFDY (SEQ ID NO: 3208) I083G062097 138-250 161-174 190-196 229-239 1-122 26-35 50-66 99-111ERGGRDGDYALDF (SEQ ID NO: 3148) I083G08 2098 141-253 164-177 193-199232-242 1-125 26-35 50-66 99-114 EGGGDAYDVAPYYFDY (SEQ ID NO: 2204)I083G09 2099 130-242 154-166 182-188 221-231 1-114 26-35 50-66 99-103DPFDY (SEQ ID NO: 3134) I083G11 2100 140-252 163-176 192-198 231-2411-124 26-35 50-66 99-113 ALLGLPSDFSYYVDV (SEQ ID NO: 3159) I083H04 2101141-253 164-177 193-199 232-242 1-125 26-35 50-66 99-114EGEGDGYNVAPYYFDY (SEQ ID NO: 3160) I083H05 2102 133-243 157-167 183-189222-232 1-117 26-35 50-66 99-106 TDYGGFDY (SEQ ID NO: 3092) I083H07 2103137-247 161-171 187-193 226-236 1-121 26-35 50-66 99-110 GGVGDSRGVFDP(SEQ ID NO: 3162) I084A03 2104 130-237 153-163 179-185 218-226 1-11426-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I084A08 2105 130-240 152-164180-186 219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I084B082106 135-242 156-166 182-188 221-231 1-119 26-35 50-66 99-108 ESLTGDAFDI(SEQ ID NO: 3116) I084C02 2107 136-243 157-167 183-189 222-232 1-12026-35 50-66 99-109 SPLHFSDAFDI (SEQ ID NO: 3120) I084D03 2108 130-240152-164 180-186 219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203)I084D05 2109 133-243 155-168 184-190 223-232 1-117 26-35 50-66 99-106EVGGAFDI (SEQ ID NO: 3157) I084E01 2110 130-237 153-163 179-185 218-2261-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I084E06 2111 130-237153-163 179-185 218-226 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203)I084E10 2112 130-237 151-161 177-183 216-226 1-114 26-35 50-66 99-103DTTDY (SEQ ID NO: 2203) I084E12 2113 130-240 152-164 180-186 219-2291-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203) I084F04 2114 130-237153-163 179-185 218-226 1-114 26-35 50-66 99-103 DTTDY (SEQ ID NO: 2203)I084F07 2115 130-237 153-163 179-185 218-226 1-114 26-35 50-66 99-103DTTDY (SEQ ID NO: 2203) I084F12 2116 135-245 157-170 186-192 225-2341-119 26-35 50-66 99-108 ESLTGDAFDI (SEQ ID NO: 3116) I084G12 2117130-240 152-164 180-186 219-229 1-114 26-35 50-66 99-103 DTTDY (SEQ IDNO: 2203) I084H02 2118 130-237 153-163 179-185 218-226 1-114 26-35 50-6699-103 DTTDY (SEQ ID NO: 2203) I099B05 2119 145-256 168-180 196-202235-245 1-129 26-35 50-66 99-118 GAHYYDRSPSHLKSYWYFDL (SEQ ID NO: 3149)I099G09 2120 138-249 161-173 189-195 228-238 1-122 26-35 50-66 99-111VGIKAAAVDNFEY (SEQ ID NO: 2197) I099H01 2121 138-248 162-172 188-194227-237 1-122 26-35 50-66 99-111 LGRNYTSSWSLDY (SEQ ID NO: 3181) I099H062122 138-249 161-173 189-195 228-238 1-122 26-35 50-66 99-111VGIKAAAVDNFEY (SEQ ID NO: 2197) I099H08 2123 144-255 167-179 195-201234-244 1-128 26-35 50-66 99-117 GGRYGYYYDGTGYVDAFDI (SEQ ID NO: 3226)I100A01 2124 136-247 159-172 188-194 227-236 1-120 26-35 50-66 99-109DNGGGTIGFDY (SEQ ID NO: 2195) I100A10 2125 140-251 163-175 191-197230-240 1-124 26-35 50-66 99-113 VRQQIADPPRSFFDP (SEQ ID NO: 3144)I100B03 2126 136-247 159-172 188-194 227-236 1-120 26-35 50-66 99-109DNGGGTIGFDY (SEQ ID NO: 2195) I100B04 2127 136-247 159-172 188-194227-236 1-120 26-35 50-66 99-109 DNGGGTIGFDY (SEQ ID NO: 2195) I100C032128 140-251 163-175 191-197 230-240 1-124 26-35 50-66 99-113VRQQIADPPRSFFDP (SEQ ID NO: 3144)

[0849]

0 SEQUENCE LISTING The patent application contains a lengthy “SequenceListing” section. A copy of the “Sequence Listing” is available inelectronic form from the USPTO web site(http://seqdata.uspto.gov/sequence.html?DocID=20030059937). Anelectronic copy of the “Sequence Listing” will also be available fromthe USPTO upon request and payment of the fee set forth in 37 CFR1.19(b)(3).

What is claimed is:
 1. An antibody that immunospecifically binds to BLyScomprising a first amino acid sequence at least 95% identical to ansecond amino acid sequence selected from the group consisting of: (a) anamino acid sequence comprising the amino acid sequence of a VHCDR of anyone of the scFvs of SEQ ID NOS:1 through 2128; and (b) an amino acidsequence comprising the amino acid sequence of a VLCDR of any one of thescFvs of SEQ ID NOS:1 through
 2128. 2. The antibody of claim 1, whereinthe second amino acid sequence consists of the amino acid sequence of aVHCDR3 of any one of the scFvs of SEQ ID NOS:2129 through
 3227. 3. Theantibody of claim 1, wherein the second amino acid sequence consists ofthe amino acid sequence of a VH domain of any one of the scFvs of SEQ IDNOS:1 through
 2128. 4. The antibody of claim 3 in which said VH domainconsists of the amino acid sequence of the VH domain of any one of thescFvs of SEQ ID NOS: 1 through
 1562. 5. The antibody of claim 4 in whichsaid antibody immunospecifically binds to both the soluble form andmembrane-bound form of BLyS.
 6. The antibody of claim 4 in which said VHdomain consists of the amino acid sequence of the VH domain of any oneof the scFvs of SEQ ID NOS: 1 through 46 and 321 through
 329. 7. Theantibody of claim 6 in which said VH domain consists of the amino acidsequence of the VH domain of any one of the scFvs of SEQ ID NOS: 2, 9,and
 327. 8. The antibody of claim 4 in which said VH domain consists ofthe amino acid sequence of the VH domain of any one of the scFvs of SEQID NOS: 834 through
 872. 9. The antibody of claim 3 in which said VHdomain consists of the amino acid sequence of the VH domain of any oneof the scFvs of SEQ ID NOS: 1563 through
 1880. 10. The antibody of claim9 in which, and in which said antibody immunospecifically binds to thesoluble form of BLyS.
 11. The antibody of claim 9 in which said VHdomain consists of the amino acid sequence of the VH domain of any oneof the scFvs of SEQ ID NOS: 1563 through
 1569. 12. The antibody of claim9 in which said VH domain consists of the amino acid sequence of the VHdomain of any one of the scFvs of SEQ ID NOS: 1570 through
 1595. 13. Theantibody of claim 3 in which said VH domain consists of the amino acidsequence of the VH domain of any one of the scFvs of SEQ ID NOS: 1881through
 2128. 14. The antibody of claim 13 in which said antibodyimmunospecifically binds to the membrane-bound form of BLyS.
 15. Theantibody of claim 13 in which said VH domain consists of the amino acidsequence of the VH domain of any one of the scFvs of SEQ ID NOS: 1881through
 1885. 16. The antibody of claim 13 in which said VH domainconsists of the amino acid sequence of the VH domain of any one of thescFvs of SEQ ID NOS: 1886 through
 1908. 17. The antibody of claim 1,wherein the second amino acid sequence consists of the amino acidsequence of a VL domain of any one of the scFvs of SEQ ID NOS: 1 through2128.
 18. The antibody of claim 17 in which said VL domain consists ofthe amino acid sequence of the VL domain of any one of the scFvs of SEQID NOS: 1 through
 1562. 19. The antibody of claim 18 in which saidantibody immunospecifically binds to both the soluble form andmembrane-bound form of BLyS.
 20. The antibody of claim 18 in which saidVL domain consists of the amino acid sequence of the VL domain of anyone of the scFvs of SEQ ID NOS: 1 through 46 and 321 through
 329. 21.The antibody of claim 20 in which said VL domain consists of the aminoacid sequence of the VH domain of any one of the scFvs of SEQ ID NOS: 2,9, and
 327. 22. The antibody of claim 18 in which said VL domainconsists of the amino acid sequence of the VL domain of any one of thescFvs of SEQ ID NOS: 834 through
 872. 23. The antibody of claim 17 inwhich said VL domain consists of the amino acid sequence of the VLdomain of any one of the scFvs of SEQ ID NOS: 1563 through
 1880. 24. Theantibody of claim 23 said antibody immunospecifically binds to thesoluble form of BLyS.
 25. The antibody of claim 23 in which said VLdomain consists of the amino acid sequence of the VL domain of any oneof the scFvs of SEQ ID NOS: 1563 through
 1569. 26. The antibody of claim23 in which said VL domain consists of the amino acid sequence of the VLdomain of any one of the scFvs of SEQ ID NOS: 1570 through
 1595. 27. Theantibody of claim 17 in which said VL domain consists of the amino acidsequence of the VL domain of any one of the scFvs of SEQ ID NOS: 1881through
 2128. 28. The antibody of claim 27 in which said antibodyimmunospecifically binds to the membrane-bound form of BLyS.
 29. Theantibody of claim 27 in which said VL domain consists of the amino acidsequence of the VL domain of any one of the scFvs of SEQ ID NOS: 1881through
 1885. 30. The antibody of claim 27 in which said VL domainconsists of the amino acid sequence of the VL domain of any one of thescFvs of SEQ ID NOS: 1886 through
 1908. 31. The antibody of claim 3,which also comprises an amino acid sequence at least 95% identical tothe amino acid sequence of a VL domain of any one of the scFvs of SEQ IDNOS:1 through
 2128. 32. The antibody of claim 31, wherein the VH and VLdomains are from the same scFv.
 33. The antibody of claim 32, whereinthe scFv is the scFv of SEQ ID NO:2.
 34. The antibody of claim 32,wherein the scFv is the scFv of SEQ ID NO:9.
 35. The antibody of claim32, wherein the scFv is the scFv of SEQ ID NO:327.
 36. The antibody ofclaim 1 wherein the first amino acid sequence is identical to the secondamino acid sequence.
 37. The antibody of claim 36 wherein the secondamino acid sequence consists of the amino acid sequence of a VH domainof any one of the scFvs of SEQ ID NOS: 1 through
 2128. 38. The antibodyof claim 36 wherein the second amino acid sequence consists of the aminoacid sequence of a VL domain of any one of the scFvs of SEQ ID NOS: 1through
 2128. 39. The antibody of claim 37 which also comprises an aminoacid sequence 100% identical to the amino acid sequence of a VL domainof any one of the scFvs of SEQ ID NOS:1 through
 2128. 40. The antibodyof claim 39, wherein the scFv is the scFv of SEQ ID NO:2.
 41. Theantibody of claim 39, wherein the scFv is the scFv of SEQ ID NO:9. 42.The antibody of claim 39, wherein the scFv is the scFv of SEQ ID NO:327.43. The antibody of claim 1, wherein the BLyS is a BLyS homotrimer. 44.The antibody of claim 43, wherein the individual protein components ofthe BLyS homotrimer consist of the mature form of BLyS.
 45. The antibodyof claim 1, wherein the BLyS is a BLyS heterotrimer.
 46. The antibody ofclaim 45, wherein the BLyS heterotrimer comprises at least one BLySpolypeptide and at least one APRIL polypeptide.
 47. The antibody ofclaim 46, wherein the BLyS polypeptide consists of the mature form ofBLyS and the APRIL polypeptide consists of the mature form of APRIL. 48.The antibody of claim 1, wherein the antibody is selected from the groupconsisting of: (a) a whole immunoglobulin molecule; (b) an scFv; (c) amonoclonal antibody; (d) a human antibody; (e) a chimeric antibody; (f)a humanized antibody; (g) a Fab fragment; (h) an Fab′ fragment; (i) anF(ab′)2; (j) an Fv; and (k) a disulfide linked Fv.
 49. The antibody ofclaim 3 or 37, which also comprises a heavy chain immunoglobulinconstant domain selected from the group consisting of: (a) a human IgMconstant domain; (b) a human IgG1 constant domain; (c) a human IgG2constant domain; (d) a human IgG3 constant domain; (e) a human IgG4constant domain; and (f) a human IgA constant domain.
 50. The antibodyof claim 17 or 38, which also comprises a light chain immunoglobulinconstant domain slecetd from the group consisting of: (a) a human Igkappa constant domain; (b) a human Ig lambda constant domain.
 51. Theantibody of claim 1, wherein the antibody has a dissociation constant(K_(D)) selected from the group consisting of: (a) a dissociationconstant (K_(D)) between 10⁻⁷ M and 10⁻⁸ M; (b) a dissociation constant(K_(D)) between 10⁻⁸ M and 10⁻⁹ M; (c) a dissociation constant (K_(D))between 10⁻⁹ M and 10⁻¹⁰ M; (d) a dissociation constant (K_(D)) between10⁻¹⁰ M and 10⁻¹¹ M; (e) a dissociation constant (K_(D)) between 10⁻¹¹ Mand 10⁻¹² M; and (f) a dissociation constant (K_(D)) between 10⁻¹² M and10⁻¹³ M.
 52. The antibody of claim 1, wherein the antibody is conjugatedto a detectable label.
 53. The antibody of claim 52, wherein thedetectable label is a radiolabel.
 54. The antibody of claim 53, whereinthe radiolabel is ¹²⁵I, ¹³¹I, ¹¹¹In, ⁹⁰Y, ⁹⁹Tc, ¹⁷⁷Lu, ¹⁶⁶Ho, or ¹⁵³Sm.55. The antibody of claim 52, wherein the detectable label is an enzyme,a fluorescent label, a luminescent label, or a bioluminescent label. 56.The antibody of claim 1, wherein the antibody is biotinylated.
 57. Theantibody of claim 1, wherein the antibody is conjugated to a therapeuticor cytotoxic agent.
 58. The antibody of claim 57, wherein thetherapeutic or cytotoxic agent is selected from the group consisting of:(a) an anti-metabolite, (b) an alkylatingagent; (c) an antibiotic; (d) agrowth factor; (e) a cytokine; (f) an anti-angiogenic agent; (g) ananti-mitotic agent; (h) an anthracycline; (i) toxin; and (j) anapoptotic agent.
 59. An antibody of claim 1, that neutralizes BLyS or afragment thereof.
 60. The antibody of claim 59, that,diminishes orabolishes the ability of BLyS or a fragment thereof to bind to itsreceptor.
 61. The antibody of claim 60, wherein the receptor is TACI.62. The antibody of claim 60, wherein the receptor is BCMA.
 63. Theantibody of claim 59, that diminishes or abolishes the ability of BLySor a fragment thereof to stimulate B cell proliferation.
 64. Theantibody of claim 59, that diminishes or abolishes the ability of BLySor a fragment thereof to stimulate immunoglobulin secretion by B cells.65. An antibody of claim 1, that enhances the activity of BLyS or afragment thereof.
 66. The antibody of claim 65, that increases theability of BLyS or a fragment thereof to bind to its receptor.
 67. Theantibody of claim 66, wherein the receptor is TACI.
 68. The antibody ofclaim 66, wherein the receptor is BCMA.
 69. The antibody of claim 65,that increases the ability of BLyS or a fragment thereof to stimulate Bcell proliferation.
 70. The antibody of claim 65, that increases theability of BLyS or a fragment thereof to stimulate immunoglobulinsecretion by B cells.
 71. The antibody of claim 1 covalently linked to aheterologous polypeptide.
 72. The antibody of claim 71, wherein theheterologous polypeptide is human serum albumin.
 73. The antibody ofclaim 1 in a pharmaceutically acceptable carrier.
 74. A kit comprisingthe antibody of claim
 1. 75. An isolated nucleic acid molecule encodingthe antibody of claim
 1. 76. A vector comprising the isolated nucleicacid molecule of claim
 75. 77. The vector of claim 76 which alsocomprises a nucleotide sequence which regulates the expression of theantibody encoded by the nucleic acid molecule.
 78. A host cellcomprising the nucleic acid molecule of claim
 77. 79. A cell lineengineered to express the antibody of claim
 1. 80. An antibody thatbinds the same epitope as the antibody of claim
 1. 81. An antibody thatcompetitively inhibits the binding of the antibody produced by the cellline having ATCCDeposit Number PTA-3239.
 82. An antibody thatcompetitively inhibits the binding of the antibody produced by the cellline having ATCCDeposit Number PTA-3240
 83. An antibody thatcompetitively inhibits the binding of the antibody produced by the cellline having ATCCDeposit Number PTA-3243.
 84. An second antibody thatreduces the binding of the antibody of claim 1 by a an increment withina percentage range selected from the group consisting of: (a) from 50%up to 60%; (b) from 60% up to 70%; (c) from 70% up to 80%; (d) from 80%up to 90%; and (e) from 90% up to 100%.
 85. An antibody thatimmunospecifically binds to BLyS, said antibody comprising an amino acidsequence of a VH domain encoded by a nucleotide sequence that hybridizesunder stringent conditions to a nucleotide sequence encoding a VH domainof an scFv comprising an amino acid sequence of any one of SEQ ID NOS: 1to
 2128. 86. An antibody that immunospecifically binds to BLyS, saidantibody comprising an amino acid sequence of a VL domain encoded by anucleotide sequence that hybridizes under stringent conditions to anucleotide sequence encoding a VL domain from an scFv comprising anamino acid sequence of any one of SEQ ID NOS: 1 to
 2128. 87. A methodfor detecting aberrant expression of BLyS protein, comprising: (a)assaying the level of BLyS expression in a first biological sample of anindividual using one or more antibodies or fragments or variants thereofof claim 1; and (b) comparing the level of BLyS assayed in biologicalsample with a standard level of BLyS expression or level of BLyS in asecond, normal biological sample; (c) wherein an increase or decrease inthe assayed level of BLyS in the first biological sample compared to thestandard level of BLyS expression or level of BLyS in a second, normalbiological sample, is indicative of aberrant expression.
 88. A methodfor diagnosing a disease or disorder associated with aberrant BLySexpression or activity, comprising: (a) administering to a subject aneffective amount of a labeled antibody of claim 1 thatimmunospecifically binds to BLyS; (b) waiting for a time intervalfollowing the administering for permitting the labeled antibody of claim1 to preferentially concentrate at sites in the subject where BLyS isexpressed; (c) determining background level; and (d) detecting thelabeled antibody of claim 1 in the subject, such that detection oflabeled antibody above the background level indicates that the subjecthas a particular disease or disorder associated with aberrant expressionof BLyS.
 89. A method of treating, preventing or ameliorating a diseaseor disorder associated with aberrant BLyS expression or activity,comprising administering to an animal in need thereof, thepharmaceutical composition of claim 73 in an amount effective to treat,prevent or ameliorate the disease or disorder.
 90. The method of claim89, wherein the disease or disorder is cancer.
 91. The method of claim89, wherein the disease or disorder of the immune system.
 92. The methodof claim 91, wherein the disease or disorder of the immune system is anautoimmune disease or disorder.
 93. The method of claim 92, wherein thedisease or disorder of the immune system is an autoimmune disease ordisorder selected from the group consisting of: (a) Systemic LupusErythematosus; and (b) Rheumatoid Arthritis.
 94. The method of claim 91,wherein the disease or disorder of the immune system is animmunodeficiency.
 95. The method of claim 92, wherein the disease ordisorder of the immune system is an immunodeficiency selected from thegroup consisting of: (a) Common Variable Immunodeficiency (CVID); and(b) AIDS.
 96. The method of claim 91, wherein the disease or disorder ofthe immune system is cancer.